Human protein tyrosine phosphatase inhibitors and method of use

ABSTRACT

The present disclosure relates to compounds effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors thereby regulating angiogenesis. The present disclosure further relates to compositions comprising said human protein tyrosine phosphatase beta (HPTP-β) inhibitors, and to methods for regulating angiogenesis.

PRIORITY

This application is a Continuation Application of U.S. application Ser.No. 12/850,026, filed Aug. 4, 2010 now U.S. Pat. No. 8,106,078, which isa Divisional Application of U.S. application Ser. No. 11/821,846, filedon Jun. 26, 2007, now U.S. Pat. No. 7,795,444, which claims the benefitof U.S. Provisional Applications Ser. Nos. 60/816,730, 60/816,731, and60/816,825 all of which were filed on Jun. 27, 2006 and the entiredisclosures of each of U.S. Provisional Applications Ser. Nos.60/816,730, 60/816,731, and 60/816,825 and U.S. application Ser. Nos.12/850,026 and 11/821,846, are all incorporated herein by reference intheir entirety.

FIELD

The present disclosure relates to compounds effective as human proteintyrosine phosphatase beta (HPTP-β) inhibitors thereby regulatingangiogenesis. The present disclosure further relates to compositionscomprising one or more human protein tyrosine phosphatase beta (HPTP-β)inhibitors, and to methods for regulating angiogenesis.

BACKGROUND

Angiogenesis, the sprouting of new blood vessels from the pre-existingvasculature, plays a crucial role in a wide range of physiological andpathological processes (Nguyen, L. L. et al., Int. Rev. Cytol., 204,1-48, (2001)). Angiogenesis is a complex process, mediated bycommunication between the endothelial cells that line blood vessels andtheir surrounding environment. In the early stages of angiogenesis,tissue or tumor cells produce and secrete pro-angiogenic growth factorsin response to environmental stimuli such as hypoxia. These factorsdiffuse to nearby endothelial cells and stimulate receptors that lead tothe production and secretion of proteases that degrade the surroundingextracellular matrix. The activated endothelial cells begin to migrateand proliferate into the surrounding tissue toward the source of thesegrowth factors (Bussolino, F., Trends Biochem. Sci., 22, 251-256,(1997)). Endothelial cells then stop proliferating and differentiateinto tubular structures, which is the first step in the formation ofstable, mature blood vessels. Subsequently, periendothelial cells, suchas pericytes and smooth muscle cells, are recruited to the newly formedvessel in a further step toward vessel maturation.

Angiogenesis is regulated by a balance of naturally occurring pro- andanti-angiogenic factors. Vascular endothelial growth factor, fibroblastgrowth factor, and angiopoeitin represent a few of the many potentialpro-angiogenic growth factors. These ligands bind to their respectivereceptor tyrosine kinases on the endothelial cell surface and transducesignals that promote cell migration and proliferation. Whereas manyregulatory factors have been identified, the molecular mechanisms ofthis process are still not fully understood.

There are many disease states driven by persistent unregulated orimproperly regulated angiogenesis. In such disease states, unregulatedor improperly regulated angiogenesis may either cause a particulardisease or exacerbate an existing pathological condition. For example,ocular neovascularization has been implicated as the most common causeof blindness and underlies the pathology of approximately 20 eyediseases. In certain previously existing conditions such as arthritis,newly formed capillary blood vessels invade the joints and destroycartilage. In diabetes, new capillaries formed in the retina invade thevitreous humor, causing bleeding and blindness. Both the growth andmetastasis of solid tumors are also angiogenesis-dependent (Folkman etal., “Tumor Angiogenesis,” Chapter 10, 206-32, in The Molecular Basis ofCancer, Mendelsohn et al., eds., W.B. Saunders, (1995)). It has beenshown that tumors which enlarge to greater than 2 mm in diameter mustobtain their own blood supply and do so by inducing the growth of newcapillary blood vessels. After these new blood vessels become embeddedin the tumor, they provide nutrients and growth factors essential fortumor growth as well as a means for tumor cells to enter the circulationand metastasize to distant sites, such as liver, lung or bone (Weidner,New Eng. J. Med., 324, 1, 1-8 (1991)). When used as drugs intumor-bearing animals, natural inhibitors of angiogenesis may preventthe growth of small tumors (O'Reilly et al., Cell, 79, 315-28 (1994)).In some protocols, the application of such inhibitors leads to tumorregression and dormancy even after cessation of treatment (O'Reilly etal., Cell, 88, 277-85 (1997)). Moreover, supplying inhibitors ofangiogenesis to certain tumors may potentiate their response to othertherapeutic regimens (Teischer et al., Int. J. Cancer, 57, 920-25(1994)).

Although many disease states are driven by persistent unregulated orimproperly regulated angiogenesis, some disease states could be treatedby increased angiogenesis. Tissue growth and repair are biologic eventswherein cellular proliferation and angiogenesis occur. Thus an importantaspect of wound repair is the revascularization of damaged tissue byangiogenesis.

Chronic, non-healing wounds are a major cause of prolonged morbidity inthe aged human population. This is especially the case in bedridden ordiabetic patients who develop severe, non-healing skin ulcers. In manyof these cases, the delay in healing is a result of inadequate bloodsupply either as a result of continuous pressure or of vascularblockage. Poor capillary circulation due to small artery atherosclerosisor venous stasis contributes to the failure to repair damaged tissue.Such tissues are often infected with microorganisms that proliferateunchallenged by the innate defense systems of the body which requirewell vascularized tissue to effectively eliminate pathogenic organisms.As a result, most therapeutic intervention centers on restoring bloodflow to ischemic tissues thereby allowing nutrients and immunologicalfactors access to the site of the wound.

Atherosclerotic lesions in large vessels may cause tissue ischemia thatcould be ameliorated by modulating blood vessel growth to the affectedtissue. For example, atherosclerotic lesions in the coronary arteriesmay cause angina and myocardial infarction that could be prevented ifone could restore blood flow by stimulating the growth of collateralarteries. Similarly, atherosclerotic lesions in the large arteries thatsupply the legs may cause ischemia in the skeletal muscle that limitsmobility and in some cases necessitates amputation, which may also beprevented by improving blood flow with angiogenic therapy.

Other diseases such as diabetes and hypertension are characterized by adecrease in the number and density of small blood vessels such asarterioles and capillaries. These small blood vessels are important forthe delivery of oxygen and nutrients. A decrease in the number anddensity of these vessels contributes to the adverse consequences ofhypertension and diabetes including claudication, ischemic ulcers,accelerated hypertension, and renal failure. These common disorders andmany other less common ailments, such as Burgers disease, could beameliorated by increasing the number and density of small blood vesselsusing angiogenic therapy.

It has been suggested that one means for regulating angiogenesis is totreat patients with a human protein tyrosine phosphatase beta (HPTP-β)inhibitor (Kruegar et al., EMBO J., 9, (1990)) and, therefore, tosatisfy this need the compounds of the present disclosure have beenprepared.

SUMMARY

The present disclosure relates to compounds having Formula (I) as shownbelow:

or pharmaceutically acceptable salts thereof, wherein the R and Z groupscan be defined by any of the various alternative descriptions offeredbelow. The compounds of Formula (I), and/or their pharmaceuticallyacceptable salts have been found to be inhibitors of human proteintyrosine phosphatase beta (HPTP-β), and hence are capable of regulatingangiogenesis in humans, so as to treat various diseases that include butare not limited to diabetic retinopathy, macular degeneration, cancer,sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget'sdisease, vein occlusion, artery occlusion, carotid obstructive disease,chronic uveitis/vitritis, mycobacterial infections, Lyme's disease,systemic lupus erythematosis, retinopathy of prematurity, Eales'disease, Behcet's disease, infections causing a retinitis orchoroiditis, presumed ocular histoplasmosis, Best's disease, myopia,optic pits, Stargardt's disease, pars planitis, chronic retinaldetachment, hyperviscosity syndrome, toxoplasmosis, trauma andpost-laser complications, diseases associated with rubeosis, andproliferative vitreoretinopathy, Crohn's disease and ulcerative colitis,psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas,Osler-Weber-Rendu disease, hereditary hemorrhagic telangiectasia, solidor blood borne tumors and acquired immune deficiency syndrome, skeletalmuscle and myocardial ischemia, stroke, coronary artery disease,peripheral vascular disease, and coronary artery disease.

The present disclosure further relates to pharmaceutical compositionscomprising one or more of the compounds of Formula (I), andpharmaceutically acceptable salts thereof.

The present disclosure also relates to methods for controllingangiogenesis, and thereby providing a treatment for diseases affected byangiogenesis, said methods comprising administering to a human aneffective amount of one or more compounds having Formula (I), andpharmaceutically acceptable salts thereof, as disclosed herein.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All documents cited are inrelevant part, incorporated herein by reference; the citation of anydocument is not to be construed as an admission that it is prior artwith respect to the present disclosure.

DETAILED DESCRIPTION

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

All percentages, ratios and proportions herein are by weight, unlessotherwise specified. All temperatures are in degrees Celsius (° C.)unless otherwise specified.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the relevant active compoundwithout causing clinically unacceptable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained.

Throughout the description and claims of this specification the word“comprise” and other forms of the word, such as “comprising” and“comprises,” means including but not limited to, and is not intended toexclude, for example, other additives, components, integers, or steps.

As used in the description and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a composition”includes mixtures of two or more such compositions, reference to “aphenylsulfamic acid” includes mixtures of two or more suchphenylsulfamic acids, reference to “the compound” includes mixtures oftwo or more such compounds, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that when a value is disclosed, then“less than or equal to” the value, “greater than or equal to the value,”and possible ranges between values are also disclosed, as appropriatelyunderstood by the skilled artisan. For example, if the value “10” isdisclosed, then “less than or equal to 10” as well as “greater than orequal to 10” is also disclosed. It is also understood that throughoutthe application data are provided in a number of different formats andthat this data represent endpoints and starting points and ranges forany combination of the data points. For example, if a particular datapoint “10” and a particular data point “15” are disclosed, it isunderstood that greater than, greater than or equal to, less than, lessthan or equal to, and equal to 10 and 15 are considered disclosed aswell as between 10 and 15. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 aredisclosed, then 11, 12, 13, and 14 are also disclosed.

An organic unit can have, for example, 1-26 carbon atoms, 1-18 carbonatoms, 1-12 carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamido, substitutedalkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

Substituted and unsubstituted linear, branched, or cyclic alkyl unitsinclude the following non-limiting examples: methyl (C₁), ethyl (C₂),n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), n-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄),cyclopentyl (C₅), cyclohexyl (C₆), and the like; whereas substitutedlinear, branched, or cyclic alkyl, non-limiting examples of whichincludes, hydroxymethyl (C₁), chloromethyl (C₁), trifluoromethyl (C₁),aminomethyl (C₁), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),1,2-difluoroethyl (C₂), 2,2,2-trifluoroethyl (C₃), 3-carboxypropyl (C₃),2,3-dihydroxycyclobutyl (C₄), and the like.

Substituted and unsubstituted linear, branched, or cyclic alkenylinclude, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),buten-4-yl (C₄), and the like; substituted linear or branched alkenyl,non-limiting examples of which include, 2-chloroethenyl (also2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl (C₄),7-hydroxy-7-methyloct-4-en-2-yl (C₉),7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like.

Substituted and unsubstituted linear or branched alkynyl include,ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃), propyn-1-yl (C₃), and2-methyl-hex-4-yn-1-yl (C₇); substituted linear or branched alkynyl,non-limiting examples of which include, 5-hydroxy-5-methylhex-3-ynyl(C₇), 6-hydroxy-6-methylhept-3-yn-2-yl (C₈),5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like.

The term “aryl” as used herein denotes organic rings that consist onlyof a conjugated planar carbon ring system with delocalized pi electrons,non-limiting examples of which include phenyl (C₆), naphthylen-1-yl(C₁₀), naphthylen-2-yl (C₁₀). Aryl rings can have one or more hydrogenatoms substituted by another organic or inorganic radical. Non-limitingexamples of substituted aryl rings include: 4-fluorophenyl (C₆),2-hydroxyphenyl (C₆), 3-methylphenyl (C₆), 2-amino-4-fluorophenyl (C₆),2-(N,N-diethylamino)phenyl (C₆), 2-cyanophenyl (C₆),2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl (C₆),8-hydroxynaphthylen-2-yl (C₁₀), 4,5-dimethoxynaphthylen-1-yl (C₁₀), and6-cyanonaphthylen-1-yl (C₁₀).

The term “heteroaryl” denotes an aromatic ring system having from 5 to10 atoms. The rings can be a single ring, for example, a ring having 5or 6 atoms wherein at least one ring atom is a heteroatom not limited tonitrogen, oxygen, or sulfur. Or “heteroaryl” can denote a fused ringsystem having 8 to 10 atoms wherein at least one of the rings is anaromatic ring and at least one atom of the aromatic ring is a heteroatomnot limited nitrogen, oxygen, or sulfur.

The following are non-limiting examples of heteroaryl rings according tothe present disclosure:

The term “heterocyclic” denotes a ring system having from 3 to 10 atomswherein at least one of the ring atoms is a heteroatom not limited tonitrogen, oxygen, or sulfur. The rings can be single rings, fused rings,or bicyclic rings. Non-limiting examples of heterocyclic rings include:

All of the aforementioned heteroaryl or heterocyclic rings can beoptionally substituted with one or more substitutes for hydrogen asdescribed herein further.

Throughout the description of the present disclosure the terms havingthe spelling “thiophene-2-yl and thiophene-3-yl” are used to describethe heteroaryl units having the respective formulae:

whereas in naming the compounds of the present disclosure, the chemicalnomenclature for these moieties are typically spelled “thiophen-2-yl andthiophen-3-yl” respectively. Herein the terms “thiophene-2-yl andthiophene-3-yl” are used when describing these rings as units ormoieties which make up the compounds of the present disclosure solely tomake it unambiguous to the artisan of ordinary skill which rings arereferred to herein.

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as “a hydrocarbyl moiety, whetheracyclic or cyclic, which has one or more hydrogen atoms replaced by asubstituent or several substituents as defined herein below.” The units,when substituting for hydrogen atoms are capable of replacing onehydrogen atom, two hydrogen atoms, or three hydrogen atoms of ahydrocarbyl moiety at a time. In addition, these substituents canreplace two hydrogen atoms on two adjacent carbons to form saidsubstituent, new moiety, or unit. For example, a substituted unit thatrequires a single hydrogen atom replacement includes halogen, hydroxyl,and the like. A two hydrogen atom replacement includes carbonyl,oximino, and the like. A two hydrogen atom replacement from adjacentcarbon atoms includes epoxy, and the like. A three hydrogen replacementincludes cyano, and the like. The term substituted is used throughoutthe present specification to indicate that a hydrocarbyl moiety, interalia, aromatic ring, alkyl chain; can have one or more of the hydrogenatoms replaced by a substituent. When a moiety is described as“substituted” any number of the hydrogen atoms may be replaced. Forexample, 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring”,(N,N-dimethyl-5-amino)octanyl is a “substituted C₈ alkyl unit,3-guanidinopropyl is a “substituted C₃ alkyl unit,” and2-carboxypyridinyl is a “substituted heteroaryl unit.”

The following are non-limiting examples of units that can substitute forhydrogen atoms on a unit:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; for example, methyl (C₁), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C₃), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein below;    -   iv) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein below;    -   v) —(CR^(14a)R^(14b))_(z)OR¹³; or example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vi) —(CR^(14a)R^(14b))_(z)C(O)R¹³; for example, —COCH₃,        —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   vii) —(CR^(14a)R^(14b))_(z)C(O)OR¹³; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   viii) —(CR^(14a)R^(14b))_(z)C(O)N(R¹³)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   ix) —(CR^(14a)R^(14b))_(z)N(R¹³)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂, and        —CH₂NH(CH₂CH₃);    -   x) halogen; —F, —Cl, —Br, and —I;    -   xi) —(CR^(14a)R^(14b))_(z)CN;    -   xii) (CR^(14a)R^(14b))_(z)NO₂;    -   xiii) —CH_(j)X_(k); wherein X is halogen, j is from 0 to 2,        j+k=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   xiv) —(CR^(14a)R^(14b))_(z)SR¹³; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xv) —(CR^(14a)R^(14b))_(z)SO₂R¹³; —SO₂H, —CH₂SO₂H, —SO₂CH₃,        —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xiii) —(CR^(14a)R^(14b))_(z)SO₃R¹³; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R¹³ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, branched, or cyclic alkyl, phenyl,        benzyl; or two R¹³ units can be taken together to form a ring        comprising 3-7 atoms; R^(14a) and R^(14b) are each independently        hydrogen or C₁-C₄ linear or branched alkyl; the index p is from        0 to 4.

The present disclosure addresses several unmet medical needs, interalia;

-   1) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder, disease, malady, or    condition wherein angiogenesis is elevated;-   2) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder, disease, malady, or    condition; and-   3) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder, disease, malady, or    condition wherein angiogenesis is decreased.

These and other unmet medical needs are resolved by the human proteintyrosine phosphatase beta (HPTP-β) inhibitors of the present disclosure,that are capable of regulating angiogenesis and thereby serving as amethod for treating elevated or diminished angiogenesis in humans or intreating diseases that are caused by insufficient regulation of humanprotein tyrosine phosphatase beta (HPTP-β).

The compounds disclosed herein include all pharmaceutically acceptablesalt forms, for example, salts of both basic groups, inter alia, amines,as well as salts of acidic groups, inter alia, sulfamic acids, andcarboxylic acids. The following are non-limiting examples of anions thatcan form salts with basic groups, such as amines: chloride, bromide,iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate,acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate,maleate, succinate, tartrate, fumarate, citrate, and the like. Thefollowing are non-limiting examples of cations that can form salts ofacidic groups, such as carboxylic acid/carboxylate units: sodium,lithium, potassium, calcium, magnesium, bismuth, and the like.

The compounds of the present disclosure are ethyl-amino substitutedphenylsulfamic acids, or their pharmaceutically acceptable salts, havingthe core structure of Compound (I) shown in the drawing below:

wherein the units R and Z can be any of the alternatives further definedand exemplified herein below. In such compounds of Formula (I), thecarbon atom bearing the amino unit has the absolute stereochemistry (S)stereochemistry as indicated in the drawing above, which typicallycorresponds to an (S) configuration at the same amine-bearing carbonatom, but which could vary depending on the nature of the R substituentgroup and the resulting priority changes.R Units

In some embodiments, the R units of the compounds of Formula (I) can besubstituted or unsubstituted heterocyclic or heteroaryl rings havingfrom 3 to 15 ring atoms. The heterocyclic or heteroaryl rings can berepresented below by the generic ring, A, in the formula:

Examples of the heterocyclic or heteroaryl “A” rings include the ringstructures

These heterocyclic or heteroaryl rings can be substituted by one or moreindependently chosen substituents represented in the generic formula byR¹⁵ units. Non-limiting examples of R¹⁵ units include:

-   -   i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for        example, methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl        (C₃), cyclopropyl (C₃), propylen-2-yl (C₃), propargyl (C₃),        n-butyl (C₄), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄),        cyclobutyl (C₄), n-pentyl (C₅), cyclopentyl (C₅), n-hexyl (C₆),        and cyclohexyl (C₆);    -   ii) substituted or unsubstituted aryl; for example, phenyl,        2-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 2-aminophenyl,        3-hydroxyphenyl, 4-trifluoromethylphenyl, and biphenyl-4-yl;    -   iii) substituted or unsubstituted heterocyclic; examples of        which are provided herein below;    -   iv) substituted or unsubstituted heteroaryl; examples of which        are provided herein below;    -   v) —(CR^(17a)R^(17b))_(q)OR¹⁶; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vi) —(CR^(17a)R^(17b))_(q)C(O)OR¹⁶; (for example, —COCH₃,        —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   vii) —(CR^(17a)R^(17b))_(q)C(O)OR¹⁶; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   viii) —(CR^(17a)R^(17b))_(q)C(O)N(R¹⁶)₂; for example, —CONH₂,        —CH₂CONH₂, CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   ix) —(CR^(17a)R^(17b))_(q)OC(O)N(R¹⁶)₂; for example, —OC(O)NH₂,        —CH₂OC(O)NH₂, —OC(O)NHCH₃, —CH₂OC(O)NHCH₃, —OC(O)N(CH₃)₂, and        —CH₂OC(O)N(CH₃)₂;    -   x) —(CR^(17a)R^(17b))_(q)N(R¹⁶)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂, and        —CH₂NH(CH₂CH₃);    -   xi) halogen: —F, —Cl, —Br, and —I;    -   xii) —CH_(m)X_(n); wherein X is halogen, m is from 0 to 2,        m+n=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   xiii) —(CR^(17a)R^(17b))_(q)CN; for example; —CN, —CH₂CN, and        —CH₂CH₂CN;    -   xiv) —(CR^(17a)R^(17b))_(q)NO₂; for example; —NO₂, —CH₂NO₂, and        —CH₂CH₂NO₂;    -   xv) —(CR^(17a)R^(17b))_(q)SO₂R¹⁶; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvi) —(CR^(17a)R^(17b))_(q)SO₃R¹⁶; for example, —SO₃H, —CH₂SO₃H,        —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R¹⁶ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, branched, or cyclic alkyl; or two        R¹⁶ units can be taken together to form a ring comprising 3-7        atoms; R^(17a) and R^(17b) are each independently hydrogen or        C₁-C₄ linear or branched alkyl; the index q is from 0 to 4.

When R¹⁵ units comprise C₁-C₁₂ linear, branched, or cyclic alkyl,alkenyl; substituted or unsubstituted C₆ or C₁₀ aryl; substituted orunsubstituted C₁-C₉ heterocyclic; or substituted or unsubstituted C₁-C₉heteroaryl; R¹⁵ units can further have one or more hydrogen atomssubstituted by R¹⁸ units. Non-limiting examples of R¹⁸ units include:

-   -   i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for        example, methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl        (C₃), cyclopropyl (C₃), propylen-2-yl (C₃), propargyl (C₃),        n-butyl (C₄), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄),        cyclobutyl (C₄), n-pentyl (C₅), cyclopentyl (C₅), n-hexyl (C₆),        and cyclohexyl (C₆);    -   ii) —(CR^(20a)R^(20b))_(q)OR¹⁹; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   iii) —(CR^(20a)R^(20b))_(q)C(O)R¹⁹; for example, —COCH₃,        —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   iv) —(CR^(20a)R^(20b))_(q)C(O)OR¹⁹; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   v) —(CR^(20a)R^(20b))_(q)C(O)N(R¹⁹)₂; for example, —CONH₂,        —CH₂CONH₂, CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   vi) —(CR^(20a)R^(20b))_(q)OC(O)N(R¹⁹)₂; for example, —OC(O)NH₂,        —CH₂OC(O)NH₂, —OC(O)NHCH₃, —CH₂OC(O)NHCH₃, —OC(O)N(CH₃)₂, and        —CH₂OC(O)N(CH₃)₂;    -   vii) —(CR^(20a)R^(20b))_(q)N(R¹⁹)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂, and        —CH₂NH(CH₂CH₃);    -   viii) halogen: —F, —Cl, —Br, and —I;    -   ix) —CH_(m)X_(n); wherein X is halogen, m is from 0 to 2, m+n=3;        for example, —CH₂F, —CF₃, —CCl₃, or —CBr₃;    -   x) —(CR^(20a)R^(20b))_(q)CN; for example; —CN, —CH₂CN, and        —CH₂CH₂CN;    -   xi) —(CR^(20a)R^(20b))_(q)NO₂; for example; —NO₂, —CH₂NO₂, and        —CH₂CH₂NO₂;    -   xii) —(CR^(20a)R^(20b))_(q)SO₂R¹⁹; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xiii) —(CR^(20a)R^(20b))_(q)SO₃R¹⁹; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R¹⁹ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, branched, or cyclic alkyl; or two        R¹⁹ units can be taken together to form a ring comprising 3-7        atoms; R^(20a) and R^(20b) are each independently hydrogen or        C₁-C₄ linear or branched alkyl; the index p is from 0 to 4.

In the description that follows, R¹⁵ and R¹⁸ units may be represented byspecific ring substitutions, for example, a ring encompassed within thedefinition of R can be depicted as either having the formula:

or as having the formula:

Both of the above formulae stand equally well for an optionallysubstituted thiazolyl ring.

R Units

R units comprise a ring having from 3 to 15 ring atoms.

R units can comprise 5-member heteroaryl rings. The following arenon-limiting examples of 5-member heteroaryl rings:

As described herein, the 5-member heteroaryl rings can be substitutedwith one or more substitutes for hydrogen, for example, with a methylgroup:

or with a substitute for hydrogen that itself is further substituted,for example:

Examples of 5-member ring R units includes thiazolyl units having theformula:

One example of a thiazolyl R unit includes thiazol-2-yl units having theformula:

wherein R² and R³ are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted C₁-C₉ heteroaryl; or

R² and R³ can be taken together to form a saturated or unsaturated ringhaving from 5 to 7 atoms.

One example of this R unit relates to units having the formula:

wherein R³ is hydrogen and R² is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), and tert-butyl (C₄).

Another example of this R unit relates to units wherein

R² is a unit chosen from methyl (C₁), ethyl (C₂), n-propyl (C₃),iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), andtert-butyl (C₄); and R³ is a unit chosen from methyl (C₁) or ethyl (C₂).Non-limiting examples of this aspect of R includes4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazol-2-yl,4-methyl-5-ethylthiazol-2-yl, and 4,5-diethylthiazol-2-yl.

A further example of this R unit relates to units wherein R³ is hydrogenand R² is a substituted alkyl unit, the substitutions chosen from:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or branchedalkyl.

Non-limiting examples of units comprising this embodiment of R includes:—CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

A yet further example of R units include units wherein R³ is hydrogenand R² is phenyl.

A still further example of R units include units wherein R³ is hydrogenand R² is a heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

One example of R includes units wherein R² is thiophene-2-yl orthiophene-3-yl.

Another example of R units includes thiazol-4-yl units having theformula:

wherein R⁴ is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C₁-C₉ heteroaryl.

An example of R units includes compounds wherein R⁴ is hydrogen.

Another example of R units includes compounds wherein R⁴ is a unitchosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄).Non-limiting examples of this aspect of R includes 2-methylthiazol-4-yl,2-ethylthiazol-4-yl, 2-(n-propyl)thiazol-4-yl, and2-(iso-propyl)thiazol-4-yl.

A further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted phenyl, non-limiting examples of whichinclude phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

A yet further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted heteroaryl, non-limiting examples of whichinclude thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and3-methyl-1,2,4-oxadiazol-5-yl.

Another example of 5-member ring R units includes substituted orunsubstituted imidazolyl units having the formula:

One example of imidazolyl R units includes imidazol-2-yl units havingthe formula:

wherein R² and R³ are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted C₁-C₉ heteroaryl; or

R² and R³ can be taken together to form a saturated or unsaturated ringhaving from 5 to 7 atoms.

One example of R units includes compounds wherein R units have theformula:

wherein R³ is hydrogen and R² is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), and tert-butyl (C₄).

Another example of R units includes compounds wherein R² is a unitchosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄); andR³ is a unit chosen from methyl (C₁) or ethyl (C₂). Non-limitingexamples of this aspect of R includes 4,5-dimethylimidazol-2-yl,4-ethyl-5-methylimidazol-2-yl, 4-methyl-5-ethylimidazol-2-yl, and4,5-diethylimidazol-2-yl.

An example of R units includes compounds wherein R³ is hydrogen and R²is a substituted alkyl unit chosen, said substitutions chosen from:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or branchedalkyl.

Non-limiting examples of units comprising this embodiment of R includes:—CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

A yet further example of R units include units wherein R³ is hydrogenand R² is phenyl.

A still further example of R units include units wherein R³ is hydrogenand R² is a heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

One example of R includes units wherein R² is thiophene-2-yl orthiophene-3-yl.

Another example of R units includes imidazol-4-yl units having theformula:

wherein R⁴ is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C₁-C₉ heteroaryl.

One example of this embodiment of R units relates to compounds whereinR⁴ is hydrogen.

An example of R units includes compounds wherein R⁴ is hydrogen.

Another example of R units includes compounds wherein R⁴ is a unitchosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄).Non-limiting examples of this aspect of R includes2-methylimidazol-4-yl, 2-ethylimidazol-4-yl, 2-(n-propyl)imidazol-4-yl,and 2-(iso-propyl)imidazol-4-yl.

A further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted phenyl, non-limiting examples of whichinclude phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

A yet further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted heteroaryl, non-limiting examples of whichinclude thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and3-methyl-1,2,4-oxadiazol-5-yl.

Further examples of 5-member ring R units are substituted orunsubstituted oxazolyl units having the formula:

One example of oxazolyl R units includes oxazol-2-yl units having theformula:

wherein R² and R³ are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted C₁-C₉ heteroaryl; or

R² and R³ can be taken together to form a saturated or unsaturated ringhaving from 5 to 7 atoms.

One example of R units includes compounds wherein R units have theformula:

wherein R³ is hydrogen and R² is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), and tert-butyl (C₄).

Another example of R units includes units wherein R² is a unit chosenfrom methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄); and R³ is aunit chosen from methyl (C₁) or ethyl (C₂). Non-limiting examples ofthis aspect of R includes 4,5-dimethyloxazol-2-yl,4-ethyl-5-methyloxazol-2-yl, 4-methyl-5-ethyloxazol-2-yl, and4,5-diethyloxazol-2-yl.

A further example of R units includes units wherein R³ is hydrogen andR² is a substituted alkyl unit chosen, said substitutions chosen from:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or branchedalkyl.

Non-limiting examples of units comprising this embodiment of R includes:—CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

A yet further example of R units include units wherein R³ is hydrogenand R² is phenyl.

A still further example of R units include units wherein R³ is hydrogenand R² is a heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

One example of R includes units wherein R² is thiophene-2-yl orthiophene-3-yl.

Another example of R units includes oxazol-4-yl units having theformula:

wherein R⁴ is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C₁-C₉ heteroaryl.

wherein R⁴ is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C₁-C₉ heteroaryl.

One example of this embodiment of R units relates to compounds whereinR⁴ is hydrogen.

An example of R units includes compounds wherein R⁴ is hydrogen.

Another example of R units includes compounds wherein R⁴ is a unitchosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄).Non-limiting examples of this aspect of R includes 2-methyloxazol-4-yl,2-ethyloxazol-4-yl, 2-(n-propyl)oxazol-4-yl, and2-(iso-propyl)oxazol-4-yl.

A further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted phenyl, non-limiting examples of whichinclude phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

A yet further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted heteroaryl, non-limiting examples of whichinclude thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and3-methyl-1,2,4-oxadiazol-5-yl.

A further example of R units relates to oxazol-5-yl units having theformula:

wherein R⁴ is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C₁-C₉ heteroaryl.

An example of R units includes compounds wherein R⁴ is hydrogen.

Another example of R units includes compounds wherein R⁴ is a unitchosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄).Non-limiting examples of this aspect of R includes 2-methyloxazol-4-yl,2-ethyloxazol-4-yl, 2-(n-propyl)oxazol-4-yl, and2-(iso-propyl)oxazol-4-yl.

A further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted phenyl, non-limiting examples of whichinclude phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

A yet further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted heteroaryl, non-limiting examples of whichinclude thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and3-methyl-1,2,4-oxadiazol-5-yl.

A yet further example of 5-member ring R units includes substituted orunsubstituted [1,2,4]oxadiazolyl units having the formula:

One example of [1,2,4]oxadiazolyl R units includes [1,2,4]oxadiazol-3-ylunits having the formula:

wherein R² is chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C₁-C₉ heteroaryl;

One example of R units includes units wherein R² is hydrogen.

Another example includes R units wherein R² is a unit chosen from methyl(C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄); and R³ is a unitchosen from methyl (C₁) or ethyl (C₂). Non-limiting examples of thisaspect of R includes 5-methyl[1,2,4]oxadiazol-2-yl,5-ethyl[1,2,4]-oxadiazol-2-yl, 5-propyl[1,2,4]oxadiazol-2-yl, and5-cyclopropyl[1,2,4]oxadiazol-2-yl.

A further example of R units includes units wherein R² is a substitutedalkyl unit chosen, said substitutions chosen from:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or branchedalkyl.

Non-limiting examples of units comprising this embodiment of R includes:—CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

A yet further example of R units includes units wherein R² is phenyl.

A still further example of R units includes units wherein R² is aheteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

Specific examples of R units include units wherein R² is thiophene-2-ylor thiophene-3-yl.

Another example of R units includes [1,2,4]oxadiazol-5-yl units havingthe formula:

wherein R⁴ is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or unsubstituted C₁-C₉ heteroaryl.

One example of R units includes compounds wherein R⁴ is hydrogen.

Another example of R units include compounds wherein R⁴ is a unit chosenfrom methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄). Non-limitingexamples of this aspect of R includes 3-methyl[1,2,4]oxadiazol-5-yl,3-ethyl[1,2,4]oxadiazol-5-yl, 3-(n-propyl)[1,2,4]oxadiazol-5-yl, and3-(iso-propyl)[1,2,4]oxadiazol-5-yl.

A further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted phenyl, non-limiting examples of whichinclude phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

A yet further example of R units includes compounds wherein R⁴ issubstituted or unsubstituted heteroaryl, non-limiting examples of whichinclude thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and3-methyl-1,2,4-oxadiazol-5-yl.

Further non-limiting examples of 5-member heteroaryl rings include:

R units can comprise 5-member heterocyclic rings. Non-limiting examplesof 5-member heterocyclic rings include:

R units can comprise 6-member heterocyclic rings. Non-limiting examplesof 6-member heterocyclic rings include:

R units can comprise 6-member heteraryl rings. Non-limiting examples of6-member heteroaryl rings include:

A example of 6-member heteroaryl rings includes pyrimidin-2-yl unitshaving the formula:

wherein R², R³ and R⁴ are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted C₁-C₉ heteroaryl; or

R² and R³ or R³ and R⁴ can be taken together to form a saturated orunsaturated ring having from 5 to 7 atoms.

Another example of R units includes units having the formula:

wherein R³ and R⁴ are both hydrogen and R² is a unit chosen from methyl(C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄).

Further examples of R units include units wherein R² and R³ are chosenfrom methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄); and R⁴ ishydrogen. Non-limiting examples of this aspect of R includes4,5-dimethylpyrimidin-2-yl, 4,5-diethylpyrimidin-2-yl,4-methyl-5-ethyl-pyrimidin-2-yl, and 4-ethyl-5-methyl-pyrimidin-2-yl.

A yet further example of R units include units wherein R⁴ is hydrogenand R² and R³ are chosen from:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or branchedalkyl.

Non-limiting examples of units comprising this embodiment of R includes:—CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

A yet further example of R units includes units wherein R² or R³ issubstituted phenyl and R⁴ is hydrogen.

A still further example of R units includes units wherein R⁴ is hydrogenand R² or R³ is a heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

The following are non-limiting examples of R units wherein R² isthiophene-2-yl and wherein R² is thiophene-3-yl thereby providing Runits that are 4-(thiophene-2-yl)pyrimidin-2-yl,5-(thiophene-2-yl)pyrimidin-2-yl, 4-(thiophene-3-yl)pyrimidin-2-yl, and5-(thiophene-2-yl)pyrimidin-3-yl.

Non-limiting examples of 6-member heteroaryl rings include:

R units can also comprise fuse ring heteroaryl units. Non-limitingexamples of R units include:

R units that are fused heteroaryl rings can be optionally substituted byone or more independently chosen substitutes for hydrogen as describedherein above.

Z Units

Z is a unit having the formula:-(L)_(n)-R¹wherein R¹ is chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched or cyclic alkyl;

iii) substituted or unsubstituted C₆ or C₁₀ aryl;

iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; or

v) substituted or unsubstituted C₁-C₉ heteroaryl rings.

One example of R¹ units includes substituted or unsubstituted phenyl (C₆aryl) units, wherein each substitution is independently chosen from:halogen, C₁-C₄ linear, branched alkyl, or cyclic alkyl, —OR¹¹, —CN,—N(R¹¹)₂, —CO₂R¹¹, —C(O)N(R¹¹)₂, —NR¹¹C(O)R¹¹, —NO₂, and —SO₂R¹¹; eachR¹¹ is independently hydrogen; substituted or unsubstituted C₁-C₄linear, branched, cyclic alkyl, alkenyl, or alkynyl; substituted orunsubstituted phenyl or benzyl; or two R¹¹ units can be taken togetherto form a ring comprising from 3-7 atoms.

Another example of R¹ units includes substituted C₆ aryl units chosenfrom phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and3,5-dimethoxyphenyl.

A further example of R¹ units includes substituted or unsubstituted C₆aryl units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl,2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl,2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl,2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, and 2,4,6-trichlorophenyl.

A yet further example of R¹ units includes substituted C₆ aryl unitschosen from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl,2,6-dimethylphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl,2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl,2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethyl-phenyl, 4-ethylphenyl,2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl,2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl,2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl,2,4,6-triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, and4-isopropylphenyl.

Another still further example of R¹ units includes substituted C₆ arylunits chosen from 2-aminophenyl, 2-(N-methylamino)phenyl,2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl,2-(N,N-diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl,3-(N,N-dimethylamino)phenyl, 3-(N-ethylamino)phenyl,3-(N,N-diethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phenyl,4-(N,N-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, and4-(N,N-diethylamino)phenyl.

R¹ can comprise heteroaryl units. Non-limiting examples of heteroarylunits include:

R¹ heteroaryl units can be substituted or unsubstituted. Non-limitingexamples of units that can substitute for hydrogen include units chosenfrom:

i) C₁-C₆ linear, branched, and cyclic alkyl;

ii) substituted or unsubstituted phenyl and benzyl;

iii) substituted of unsubstituted C₁-C₉ heteroaryl;

iv) —C(O)R⁹; and

v) —NHC(O)R⁹;

wherein R⁹ is C₁-C₆ linear and branched alkyl; C₁-C₆ linear and branchedalkoxy; or —NHCH₂C(O)R¹⁰; R¹⁰ is chosen from hydrogen, methyl, ethyl,and tert-butyl.

An example of R¹ relates to units substituted by an alkyl unit chosenfrom methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,and tert-butyl.

Another example of R¹ includes units that are substituted by substitutedor unsubstituted phenyl and benzyl, wherein the phenyl and benzylsubstitutions are chosen from one or more:

i) halogen;

ii) C₁-C₃ alkyl;

iii) C₁-C₃ alkoxy;

iv) —CO₂R¹¹; and

v) —NHCOR¹⁶;

wherein R¹¹ and R¹⁶ are each independently hydrogen, methyl, or ethyl.

Another example of R¹ relates to phenyl and benzyl units substituted bya carboxy unit having the formula —C(O)R⁹; R⁹ is chosen from methyl,methoxy, ethyl, and ethoxy.

A further example of R¹ includes phenyl and benzyl units substituted byan amide unit having the formula —NHC(O)R⁹; R⁹ is chosen from methyl,methoxy, ethyl, ethoxy, tert-butyl, and tert-butoxy.

A yet further example of R¹ includes phenyl and benzyl units substitutedby one or more fluoro or chloro units.

L is a linking unit chosen from:

i) —C(O)NH[C(R^(5a)R^(5b))]_(w)—;

ii) —C(O)[C(R^(6a)R^(6b))]_(x)—;

iii) —C(O)[C(R^(7a)R^(7b))]_(y)C(O)—;

iv) —SO₂[C(R^(8a)R^(8b))]_(z)—,

wherein R^(5a), R^(5b), R^(6a), R^(6b), R^(7a), R^(7b), R^(8a), andR^(8b) are each independently:

i) hydrogen;

ii) C₁-C₄ substituted or unsubstituted linear or branched alkyl;

iii) substituted or unsubstituted aryl;

iv) substituted or unsubstituted heterocyclic rings;

v) substituted or unsubstituted C₁-C₉ heteroaryl rings;

and the indices w, x, y, and z are each independently from 1 to 4. Thelinking group may be present, i.e. when the index n is equal to 1, orabsent when the index n is equal to 0, for example, the linking unit isabsent in Category V compounds further described herein below.

One example of L units includes linking units having the formula:—C(O)[C(R^(6a)R^(6b))]_(x)—wherein R^(6a) is hydrogen, substituted or unsubstituted phenyl, andsubstituted or unsubstituted heteroaryl, said substitutions for phenyland heteroaryl are chosen from:

i) C₁-C₆ linear, branched, and cyclic alkyl;

ii) substituted or unsubstituted phenyl and benzyl;

iii) substituted of unsubstituted C₁-C₉ heteroaryl;

iv) —C(O)R¹⁶; and

v) —NHC(O)R¹⁶;

wherein R¹⁶ is C₁-C₆ linear and branched alkyl; C₁-C₆ linear andbranched alkoxy; or —NHCH₂C(O)R¹⁷; R¹⁷ is chosen from hydrogen, methyl,ethyl, and tert-butyl; the index x is 1 or 2.

Another example of L units includes units wherein a first R^(6a) unitchosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and3,5-dimethoxyphenyl; a second R^(6a) unit is hydrogen and R^(6b) unitsare hydrogen. For example a linking unit having the formula:

A further example of L includes a first R^(6a) unit as depicted hereinabove that is a substituted or unsubstituted heteroaryl unit asdescribed herein above.

A yet further example of L includes units having the formula:—C(O)[C(R^(6a)R^(6b))]_(x)—;wherein R^(6a) and R^(6b) are hydrogen and the index x is equal to 1 or2; said units chosen from:

i) —C(O)CH₂—; and

ii) —C(O)CH₂CH₂—.

Another example of L units includes units having the formula:—C(O)[C(R^(7a)R^(7b))]_(y)C(O)—;wherein R^(7a) and R^(7b) are hydrogen and the index x is equal to 1 or2; said units chosen from:

i) —C(O)CH₂C(O)—; and

ii) —C(O)CH₂CH₂C(O)—.

A still further example of L units includes units having the formula:—C(O)NH[C(R^(5a)R^(5b))]_(w)—;wherein R^(5a) and R^(5b) are hydrogen and the index w is equal to 0, 1or 2; said units chosen from:

ii) —C(O)NH—;

ii) —C(O)NHCH₂—; and

iii) —C(O)NHCH₂CH₂—.

A yet still further example of L units includes units having theformula:—SO₂[C(R^(8a)R^(8b))]_(z)—;wherein R^(8a) and R^(8b) are hydrogen and the index z is equal to 0, 1or 2; said units chosen from:

ii) —SO₂—;

ii) —SO₂CH₂—; and

iii) —SO₂CH₂CH₂—.

A described herein above the compounds of the present invention includesall pharmaceutically acceptable salt forms. A compound having theformula:

can form salts, for example, a salt of the sulfonic acid:

The compounds can also exist in a zwitterionic form, for example:

as a salt of a strong acid, for example:

The analogs (compounds) of the present disclosure are arranged intoseveral Categories to assist the formulator in applying a rationalsynthetic strategy for the preparation of analogs which are notexpressly exampled herein. The arrangement into categories does notimply increased or decreased efficacy for any of the compositions ofmatter described herein.

The first aspect of Category I of the present disclosure relates to2-(thiazol-2-yl) compounds having the formula:

wherein R¹, R², R³, and L are further defined herein in Table I hereinbelow.

TABLE I No. L R¹ R² R³ 1 —C(O)CH₂— phenyl —CH₃ —H 2 —C(O)CH₂—2-fluorophenyl —CH₃ —H 3 —C(O)CH₂— 3-fluorophenyl —CH₃ —H 4 —C(O)CH₂—4-fluorophenyl —CH₃ —H 5 —C(O)CH₂— 2,3-difluorophenyl —CH₃ —H 6—C(O)CH₂— 3,4-difluorophenyl —CH₃ —H 7 —C(O)CH₂— 3,5-difluorophenyl —CH₃—H 8 —C(O)CH₂— 2-chlorophenyl —CH₃ —H 9 —C(O)CH₂— 3-chlorophenyl —CH₃ —H10 —C(O)CH₂— 4-chlorophenyl —CH₃ —H 11 —C(O)CH₂— 2,3-dichlorophenyl —CH₃—H 12 —C(O)CH₂— 3,4-dichlorophenyl —CH₃ —H 13 —C(O)CH₂—3,5-dichlorophenyl —CH₃ —H 14 —C(O)CH₂— 2-hydroxyphenyl —CH₃ —H 15—C(O)CH₂— 3-hydroxyphenyl —CH₃ —H 16 —C(O)CH₂— 4-hydroxyphenyl —CH₃ —H17 —C(O)CH₂— 2-methoxyphenyl —CH₃ —H 18 —C(O)CH₂— 3-methoxyphenyl —CH₃—H 19 —C(O)CH₂— 4-methoxyphenyl —CH₃ —H 20 —C(O)CH₂— 2,3-dimethoxyphenyl—CH₃ —H 21 —C(O)CH₂— 3,4-dimethoxyphenyl —CH₃ —H 22 —C(O)CH₂—3,5-dimethoxyphenyl —CH₃ —H 23 —C(O)CH₂— phenyl —CH₂CH₃ —H 24 —C(O)CH₂—2-fluorophenyl —CH₂CH₃ —H 25 —C(O)CH₂— 3-fluorophenyl —CH₂CH₃ —H 26—C(O)CH₂— 4-fluorophenyl —CH₂CH₃ —H 27 —C(O)CH₂— 2,3-difluorophenyl—CH₂CH₃ —H 28 —C(O)CH₂— 3,4-difluorophenyl —CH₂CH₃ —H 29 —C(O)CH₂—3,5-difluorophenyl —CH₂CH₃ —H 30 —C(O)CH₂— 2-chlorophenyl —CH₂CH₃ —H 31—C(O)CH₂— 3-chlorophenyl —CH₂CH₃ —H 32 —C(O)CH₂— 4-chlorophenyl —CH₂CH₃—H 33 —C(O)CH₂— 2,3-dichlorophenyl —CH₂CH₃ —H 34 —C(O)CH₂—3,4-dichlorophenyl —CH₂CH₃ —H 35 —C(O)CH₂— 3,5-dichlorophenyl —CH₂CH₃ —H36 —C(O)CH₂— 2-hydroxyphenyl —CH₂CH₃ —H 37 —C(O)CH₂— 3-hydroxyphenyl—CH₂CH₃ —H 38 —C(O)CH₂— 4-hydroxyphenyl —CH₂CH₃ —H 39 —C(O)CH₂—2-methoxyphenyl —CH₂CH₃ —H 40 —C(O)CH₂— 3-methoxyphenyl —CH₂CH₃ —H 41—C(O)CH₂— 4-methoxyphenyl —CH₂CH₃ —H 42 —C(O)CH₂— 2,3-dimethoxyphenyl—CH₂CH₃ —H 43 —C(O)CH₂— 3,4-dimethoxyphenyl —CH₂CH₃ —H 44 —C(O)CH₂—3,5-dimethoxyphenyl —CH₂CH₃ —H 45 —C(O)CH₂CH₂— phenyl —CH₃ —H 46—C(O)CH₂CH₂— 2-fluorophenyl —CH₃ —H 47 —C(O)CH₂CH₂— 3-fluorophenyl —CH₃—H 48 —C(O)CH₂CH₂— 4-fluorophenyl —CH₃ —H 49 —C(O)CH₂CH₂—2,3-difluorophenyl —CH₃ —H 50 —C(O)CH₂CH₂— 3,4-difluorophenyl —CH₃ —H 51—C(O)CH₂CH₂— 3,5-difluorophenyl —CH₃ —H 52 —C(O)CH₂CH₂— 2-chlorophenyl—CH₃ —H 53 —C(O)CH₂CH₂— 3-chlorophenyl —CH₃ —H 54 —C(O)CH₂CH₂—4-chlorophenyl —CH₃ —H 55 —C(O)CH₂CH₂— 2,3-dichlorophenyl —CH₃ —H 56—C(O)CH₂CH₂— 3,4-dichlorophenyl —CH₃ —H 57 —C(O)CH₂CH₂—3,5-dichlorophenyl —CH₃ —H 58 —C(O)CH₂CH₂— 2-hydroxyphenyl —CH₃ —H 59—C(O)CH₂CH₂— 3-hydroxyphenyl —CH₃ —H 60 —C(O)CH₂CH₂— 4-hydroxyphenyl—CH₃ —H 61 —C(O)CH₂CH₂— 2-methoxyphenyl —CH₃ —H 62 —C(O)CH₂CH₂—3-methoxyphenyl —CH₃ —H 63 —C(O)CH₂CH₂— 4-methoxyphenyl —CH₃ —H 64—C(O)CH₂CH₂— 2,3-dimethoxyphenyl —CH₃ —H 65 —C(O)CH₂CH₂—3,4-dimethoxyphenyl —CH₃ —H 66 —C(O)CH₂CH₂— 3,5-dimethoxyphenyl —CH₃ —H67 —C(O)CH₂CH₂— phenyl —CH₂CH₃ —H 68 —C(O)CH₂CH₂— 2-fluorophenyl —CH₂CH₃—H 69 —C(O)CH₂CH₂— 3-fluorophenyl —CH₂CH₃ —H 70 —C(O)CH₂CH₂—4-fluorophenyl —CH₂CH₃ —H 71 —C(O)CH₂CH₂— 2,3-difluorophenyl —CH₂CH₃ —H72 —C(O)CH₂CH₂— 3,4-difluorophenyl —CH₂CH₃ —H 73 —C(O)CH₂CH₂—3,5-difluorophenyl —CH₂CH₃ —H 74 —C(O)CH₂CH₂— 2-chlorophenyl —CH₂CH₃ —H75 —C(O)CH₂CH₂— 3-chlorophenyl —CH₂CH₃ —H 76 —C(O)CH₂CH₂— 4-chlorophenyl—CH₂CH₃ —H 77 —C(O)CH₂CH₂— 2,3-dichlorophenyl —CH₂CH₃ —H 78 —C(O)CH₂CH₂—3,4-dichlorophenyl —CH₂CH₃ —H 79 —C(O)CH₂CH₂— 3,5-dichlorophenyl —CH₂CH₃—H 80 —C(O)CH₂CH₂— 2-hydroxyphenyl —CH₂CH₃ —H 81 —C(O)CH₂CH₂—3-hydroxyphenyl —CH₂CH₃ —H 82 —C(O)CH₂CH₂— 4-hydroxyphenyl —CH₂CH₃ —H 83—C(O)CH₂CH₂— 2-methoxyphenyl —CH₂CH₃ —H 84 —C(O)CH₂CH₂— 3-methoxyphenyl—CH₂CH₃ —H 85 —C(O)CH₂CH₂— 4-methoxyphenyl —CH₂CH₃ —H 86 —C(O)CH₂CH₂—2,3-dimethoxyphenyl —CH₂CH₃ —H 87 —C(O)CH₂CH₂— 3,4-dimethoxyphenyl—CH₂CH₃ —H 88 —C(O)CH₂CH₂— 3,5-dimethoxyphenyl —CH₂CH₃ —H

The compounds encompassed within the first aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in Scheme Iand described in Example 1 herein below.

Example 1{4-[2-(S)-(4-Ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]phenyl}sulfamicacid (5)

Preparation of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl]carbamic acidtert-butyl ester (1): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid andN-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwiseiso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at0° C. for 20 minutes. after which NH₃ (g) is passed through the reactionmixture for 30 minutes at 0° C. The reaction mixture is concentrated andthe residue dissolved in EtOAc, washed successively with 5% citric acid,water, 5% NaHCO₃, water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to a residue that is triturated with a mixture ofEtOAc/petroleum ether to provide 2.2 g (74% yield) of the desiredproduct as a white solid.

Preparation of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]carbamic acidtert-butyl ester (2): To a solution of[1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester,1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent(0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours andconcentrated to a residue that is purified over silica to provide 0.350g (83% yield) of the desired product. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s,1H), 8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70(d, J=7.2 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s,9H).

Preparation of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl aminehydrobromide (3): A mixture of[2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butylester, 2, (10 g, 30.7 mmol) and 1-bromo-2-butanone (90%, 3.8 mL, 33.8mmol) in CH₃CN (500 mL) is refluxed for 18 hours. The reaction mixtureis cooled to room temperature and diethyl ether is added to the solutionand the precipitate which forms is removed by filtration to afford 7.47g of the desired product. ESI+MS 278 (M+1).

Preparation ofN-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide(4): To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamine hydrobromide, 3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g,1.4 mmol) and 1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF(10 mL) at 0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDCI) (0.268 g, 1.4 mmol) followed by triethylamine (0.60 mL, 4.2mmol). The mixture is stirred at 0° C. for 30 minutes then at roomtemperature overnight. The reaction mixture is diluted with water andextracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO₃, water and brine, and dried over Na₂SO₄.The solvent is removed in vacuo to afford 0.260 g (60% yield) of thedesired product which is used without further purification. ESI+MS 396(M+1).

Preparation of{4-[2-(S)-(4-ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]-phenyl}sulfamicacid (5):N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide,4, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.177 g, 1.23). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (10 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 0.136 g of the desired product as theammonium salt. ¹H NMR (CD₃OD) δ 8.60 (d, 1H, J=8.1 Hz), 7.33-7.23 (m,3H), 7.16-7.00 (m, 6H), 5.44-5.41 (m, 1H), 3.28 (1H, A of ABX, obscuredby solvent), 3.03 (1H, B of ABX, J=14.1, 9.6 Hz), 2.80 (q, 2H, J=10.5,7.8 Hz) 1.31 (t, 3H, J=4.6 Hz).

The following is a general procedure for isolating the final compound asa free acid.

Reduction of the aryl nitro group to free a amine:

To a Parr hydrogenation vessel is charged the nitro compound [forexample, intermediate 4] (1.0 eq) and Pd/C (10% Pd on C, 50% wet,Degussa-type E101 NE/W, 2.68 g, 15 wt %) as solids. MeOH (15 mL/g) isadded to provide a suspension. The vessel is put on a Parr hydrogenationapparatus. The vessel is submitted to a fill/vacuum evacuate processwith N₂ (3×20 psi) to inert, followed by the same procedure with H₂(3×40 psi). The vessel is filled with H₂ and the vessel is shaken under40 psi H₂ for ˜40 hr. The vessel is evacuated and the atmosphere ispurged with N₂ (5×20 psi). An aliquot is filtered and analyzed by HPLCto insure complete conversion. The suspension is filtered through a padof CELITE™ to remove the catalyst, and the homogeneous yellow filtrateis concentrated by rotary evaporation to afford the desired productwhich is used without further purification.

Preparation of free sulfamic acid: A 100 mL RBF is charged with the freeamine (1.0 eq) prepared in the step described herein above. Acetonitrile(5 mL/g) is added and the yellow suspension which is typically yellow toorange in color is stirred at room temperature. A second 3-necked 500 mLRBF is charged with SO₃. pyr (1.4 eq) and acetonitrile (5 mL/g) and thesuspension is stirred at room temperature. Both suspensions are gentlyheated until the reaction solution containing the amine becomes orangeto red-orange in color (typically at about 40-45° C.). This substratecontaining solution is poured in one portion into the stirringsuspension of SO₃. pyr at 35° C. The resulting opaque mixture is stirredvigorously while allowed to slowly cool to room temperature. Afterstirring for 45 min, or once the reaction is determined to be completeby HPLC, water (20 mL/g) is added to the colored suspension to provide ahomogeneous solution having a pH of approximately 2.4. ConcentratedH₃PO₄ is added slowly to lower the pH to approximately 1.4. During thispH adjustment, an off-white precipitate typically forms and the solutionis stirred at room temperature for an additional hour. The suspension isfiltered and the filter cake is washed with the filtrate. The filtercake is air-dried overnight to afford the desired product as the freeacid.

The following are non-limiting examples of the first aspect of CategoryI of the present disclosure.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 8.65 (d, 1H, J=8.4 Hz), 7.29-7.15 (m, 1H),7.13-7.03 (m, 7H), 5.46-5.42 (m, 1H), 3.64-3.51 (m, 2H), 3.29 (1H), 3.04(1H, B of ABX, J=13.8, 9.6 Hz), 2.81 (q, 2H, J=15.6, 3.9 Hz), 1.31 (t,3H, J=7.8 Hz). ¹⁹F NMR (CD₃OD) δ 43.64.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamicacid

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 8.74 (d, 1H, J=8.4 Hz), 7.32 (q, 1H, J=6.6, 14.2Hz), 7.10-6.91 (m, 8H), 5.47-5.40 (m, 1H), 3.53 (s, 2H), 3.30 (1H), 3.11(1H, B of ABX, J=9.6, 14.1 Hz), 2.80 (q, 2H, J=6.6, 15.1 Hz), 1.31 (t,3H, J=7.8 Hz). ¹⁹F NMR δ 47.42.

(S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 7.16-7.05 (m, 5H), 6.85-6.80 (m, 1H), 5.48-5.43(m, 1H), 3.63 (s, 2H), 3.38 (1H, A of ABX, obscured by solvent), 3.03(1H), 2.80 (q, H, J=15.1, 7.8 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 8.75 (d, 1H, J=7.8 Hz), 7.23-7.04 (m, 6H),6.88-6.84 (m, 1H), 5.44-5.40 (m, 1H), 3.49 (s, 2H), 3.34 (1H), 3.02 (1H,B of ABX, J=14.1, 9.9 Hz), 2.80 (q, 2H, J=15.1, 7.8 Hz), 1.31 (t, 1H,J=7.5 Hz). ¹⁹F NMR (CD₃OD) δ 22.18, 19.45.

(S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (CD3OD) δ 7.39-7.36 (m, 1H), 7.27-7.21 (m, 2H), 7.15-6.98(m, 5H), 5.49-5.44 (m, 1H), 3.69 (d, 2H, J=11.7 Hz), 3.32 (1H), 3.04(1H, B of ABX, J=9.3, 13.9 Hz), 2.80 (q, 2H, J=7.8, 15.3 Hz), 1.31 (t,3H, J=7.5 Hz).

(S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (CD3OD) δ 7.33-7.23 (m, 3H), 7.13-7.03 (m, 5H), 5.43 (q,1H, J=5.1, 9.6 Hz), 3.51 (s, 2H), 3.29 (1H), 3.03 (1H, B of ABX, J=9.9,14.1 Hz), 2.80 (q, 2H, J=7.5, 15 Hz), 1.31 (t, 3H, J=7.8 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 7.16-7.08 (m, 3H), 7.03-7.00 (m, 3H), 6.70-6.63(m, 2H), 5.42-5.40 (m, 1H), 3.44 (s, 2H), 3.28 (1H, A of ABX, obscuredby solvent), 3.04 (B of ABX, J=14.1, 9.6 Hz), 2.89 (q, 2H, J=15, 7.5Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 8.00 (d, 1H, J=7.8 Hz), 7.26 (t, 1H, J=13.2 Hz),7.09-7.05 (m, 4H), 7.01 (s, 1H), 6.91-6.89 (m, 4H), 5.44-5.39 (m, 1H),3.71 (s, 3H), 3.52 (s, 2H), 3.26 (1H, A of ABX, J=14.1, 5.1 Hz), 3.06(1H B of ABX, J=13.8, 8.4 Hz), 2.80 (q, 2H, J=8.1, 15.6 Hz), 1.31 (t,3H, J=1.2 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)acetamido]ethyl}phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 8.58 (d, 1H, J=8.1 Hz), 7.21 (t, 1H, J=7.8 Hz),7.12-7.02 (m, 4H), 6.81 (s, 2H), 6.72 (d, 1H, J=7.5 Hz), 5.45-5.40 (m,1H), 3.79 (s, 3H), 3.50 (s, 2H), 3.29 (1H, A of ABX, obscured bysolvent), 3.08 (1H, B of ABX, J=11.8, 5.1 Hz), 2.80 (q, 2H, J=15, 7.5Hz), 1.31 (t, 3H, J=6.6 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.56 (d, 1H, J=8.4 Hz), 7.25-6.98 (m, 9H),5.43-5.38 (m, 1H), 3.26 (1H, A of ABX, J=14.1, 9.6 Hz), 2.97 (1H, B ofABX, J=10.9, 3 Hz), 2.58-2.76 (m, 3H), 2.98 (q, 2H, J=13.8, 7.2 Hz),1.29 (t, 3H, J=8.7 Hz).

(S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.12-7.03 (m, 3H), 6.91 (d, 1H, J=8.4 Hz), 6.82(s, 1H), 6.66 (d, 1H, J=2.1 Hz), 6.63 (d, 1H, J=2.1 Hz), 5.43 (m, 1H),3.84 (s, 3H), 3.80 (s, 3H), 3.45 (s, 2H), 3.30 (1H), 3.03 (1H, B of ABX,J=14.1, 9.6 Hz), 2.79 (q, 2H, J=15.1, 7.2 Hz), 1.30 (t, 3H, J=7.2 Hz).

(S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.31 (d, 1H, J=7.8 Hz), 7.11-6.93 (m, 6H), 6.68(d, 1H, J=7.5 Hz), 5.49-5.40 (m, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 3.55(s, 2H), 3.26 (1H, A of ABX, obscured by solvent), 3.06 (1H, B of ABX,J=13.9, 9 Hz), 2.80 (q, 2H, J=14.8, 7.5 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (CD3OD) δ 7.27-7.18 (m, 3H), 7.13-7.08 (m, 5H), 7.01 (s,1H), 5.39 (q, 1H, J=5.1, 9.4 Hz), 3.28 (1H, A of ABX, J=5.1, 14.1 Hz),2.97 (1H, B of ABX, J=9.3, 13.9 Hz), 2.88-2.76 (m, 4H), 2.50 (t, 2H,J=8.1 Hz), 1.31 (t, 3H, J=7.8 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 7.18-7.08 (m, 6H), 6.92 (d, 1H, J=8.1 Hz), 6.82(t, 1H, J=7.5 Hz), 5.40-5.35 (m, 1H), 3.25 (1H, A of ABX, J=15, 5.4 Hz),3.00 (1H, B of ABX, J=10.5, 7.5 Hz), 2.88-2.76 (m, 4H), 2.47 (q, 2H,J=9.1, 6 Hz), 1.31 (t, 3H, J=7.8 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 7.19-7.00 (m, 5H), 6.75 (s, 1H), 6.73 (s, 1H),5.42-5.37 (m, 1H), 3.76 (s, 3H), 3.25 (1H, A of ABX, J=13.9, 5.4 Hz),2.98 (1H, B of ABX, J=14.1, 9.6 Hz), 2.86-2.75 (m, 4H), 2.48 (q, 2H,J=11.7, 1.2 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 7.13-6.99 (m, 7H), 6.82-6.78 (m, 2H), 5.42-5.37(m, 1H), 3.33 (s, 3H), 3.23 (1H), 2.97 (1H, B of ABX, J=13.3, 11.4 Hz),2.83-2.75 (m, 4H), 2.49 (q, 2H, J=6.4, 3.3 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.14 (s, 4H), 7.08 (s, 1H), 5.56-5.51 (m, 1H),4.34 (d, 2H, J=16.2 Hz), 3.88 (d, 2H, J=17.6 Hz), 3.59-3.40 (m, 3H),3.26-3.14 (m, 3H), 2.98 (1H, B of ABX, J=10.8, 13.9 Hz), 2.82 (q, 2H,J=6.9, 15 Hz), 1.32 (t, 3H, J=7.5 Hz), 1.21 (t, 3H, J=7.2 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.13 (s, 1H), 7.06-7.02 (m, 4H), 6.95 (s, 1H),5.42-5.31 (m, 1H), 4.43-4.18 (dd, 2H, J=16.5 Hz), 3.24-2.93 (m, 2H),2.74-2.69 (q, 2H, J=7.3 Hz), 1.79 (s, 3H), 1.22 (t, 3H, J=7.5 Hz).

(S)-4-[2-(benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.25 (d, 1H, J=6.5 Hz), 7.13 (s, 1H), 7.06 (d,2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 6.91 (s, 1H), 6.76 (d, 1H, J=8.1Hz), 5.90 (s, 2H), 5.48 (q, 1H, J=5.0 Hz), 3.32-3.24 (m, 2H), 3.07-2.99(m, 2H), 2.72 (q, 2H, J=7.5 Hz), 1.21 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H(CD₃OD): δ 7.10-7.01 (m, 5H), 5.41 (t, 1H, J=6.9 Hz), 3.58 (s,2H), 3.33-3.01 (m, 2H), 2.82-2.75 (q, 2H, J=7.5 Hz), 2.59 (s, 3H), 2.23(s, 3H), 1.30 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamido]-2-(4-methylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 8.71-8.68 (d, 1H, J=8.4 Hz), 7.10-7.03 (m, 4H), 7.01(s, 1H), 5.41 (m, 1H), 3.59 (s, 1H), 3.34-2.96 (m, 2H), 2.59 (s, 3H),2.40 (s, 3H), 2.23 (s, 3H).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}phenyl-sulfamicacid: ¹H(CD₃OD): δ 7.67-7.65 (m, 1H), 7.49-7.47 (m, 1H), 7.14-7.08 (m,4H), 7.04 (s, 1H), 5.46-5.41 (q, 1H, J=5.1 Hz), 3.58 (s, 2H), 3.30-3.25(m, 3H), 3.02-2.67 (m, 5H), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamido]ethyl}phenyl-sulfamicacid: ¹H(CD₃OD) δ 7.04-6.91 (m, 6H), 5.32 (t, 1H, J=5.4 Hz), 3.25-2.90(m, 2H), 2.71-2.61 (m, 4H) 1.93 (s, 2H) 1.22-1.14 (m, 6H).

The second aspect of Category I of the present disclosure relates to2-(thiazol-4-yl) compounds having the formula:

wherein R¹, R⁴, and L are further defined herein in Table II hereinbelow.

TABLE II No. L R¹ R⁴ 89 —C(O)CH₂— phenyl methyl 90 —C(O)CH₂— phenylethyl 91 —C(O)CH₂— phenyl phenyl 92 —C(O)CH₂— phenyl thiophene- 2-yl 93—C(O)CH₂— phenyl thiazol-2-yl 94 —C(O)CH₂— phenyl oxazol-2-yl 95—C(O)CH₂— phenyl isoxazol-3-yl 96 —C(O)CH₂— 3-chlorophenyl methyl 97—C(O)CH₂— 3-chlorophenyl ethyl 98 —C(O)CH₂— 3-chlorophenyl phenyl 99—C(O)CH₂— 3-chlorophenyl thiophene- 2-yl 100 —C(O)CH₂— 3-chlorophenylthiazol-2-yl 101 —C(O)CH₂— 3-chlorophenyl oxazol-2-yl 102 —C(O)CH₂—3-chlorophenyl isoxazol-3-yl 103 —C(O)CH₂— 3-methoxyphenyl methyl 104—C(O)CH₂— 3-methoxyphenyl ethyl 105 —C(O)CH₂— 3-methoxyphenyl phenyl 106—C(O)CH₂— 3-methoxyphenyl thiophene- 2-yl 107 —C(O)CH₂— 3-methoxyphenylthiazol-2-yl 108 —C(O)CH₂— 3-methoxyphenyl oxazol-2-yl 109 —C(O)CH₂—3-methoxyphenyl isoxazol-3-yl 110 —C(O)CH₂— 3-fluorophenyl methyl 111—C(O)CH₂— 3-fluorophenyl ethyl 112 —C(O)CH₂— 3-fluorophenyl phenyl 113—C(O)CH₂— 3-fluorophenyl thiophene- 2-yl 114 —C(O)CH₂— 3-fluorophenylthiazol-2-yl 115 —C(O)CH₂— 3-fluorophenyl oxazol-2-yl 116 —C(O)CH₂—3-fluorophenyl isoxazol-3-yl 117 —C(O)CH₂— 2,5-dimethylthiazol-4-ylmethyl 118 —C(O)CH₂— 2,5-dimethylthiazol-4-yl ethyl 119 —C(O)CH₂—2,5-dimethylthiazol-4-yl phenyl 120 —C(O)CH₂— 2,5-dimethylthiazol-4-ylthiophene- 2-yl 121 —C(O)CH₂— 2,5-dimethylthiazol-4-yl thiazol-2-yl 122—C(O)CH₂— 2,5-dimethylthiazol-4-yl oxazol-2-yl 123 —C(O)CH₂—2,5-dimethylthiazol-4-yl isoxazol-3-yl 124 —C(O)CH₂—2,4-dimethylthiazol-5-yl methyl 125 —C(O)CH₂— 2,4-dimethylthiazol-5-ylethyl 126 —C(O)CH₂— 2,4-dimethylthiazol-5-yl phenyl 127 —C(O)CH₂—2,4-dimethylthiazol-5-yl thiophene- 2-yl 128 —C(O)CH₂—2,4-dimethylthiazol-5-yl thiazol-2-yl 129 —C(O)CH₂—2,4-dimethylthiazol-5-yl oxazol-2-yl 130 —C(O)CH₂—2,4-dimethylthiazol-5-yl isoxazol-3-yl 131 —C(O)CH₂— 4-ethylthiazol-2-ylmethyl 132 —C(O)CH₂— 4-ethylthiazol-2-yl ethyl 133 —C(O)CH₂—4-ethylthiazol-2-yl phenyl 134 —C(O)CH₂— 4-ethylthiazol-2-yl thiophene-2-yl 135 —C(O)CH₂— 4-ethylthiazol-2-yl thiazol-2-yl 136 —C(O)CH₂—4-ethylthiazol-2-yl oxazol-2-yl 137 —C(O)CH₂— 4-ethylthiazol-2-ylisoxazol-3-yl 138 —C(O)CH₂— 3-methyl-1,2,4-oxadiazol-5-yl methyl 139—C(O)CH₂— 3-methyl-1,2,4-oxadiazol-5-yl ethyl 140 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl phenyl 141 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiophene- 2-yl 142 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl 143 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl 144 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl 145 —C(O)CH₂CH₂— phenylmethyl 146 —C(O)CH₂CH₂— phenyl ethyl 147 —C(O)CH₂CH₂— phenyl phenyl 148—C(O)CH₂CH₂— phenyl thiophene- 2-yl 149 —C(O)CH₂CH₂— phenyl thiazol-2-yl150 —C(O)CH₂CH₂— phenyl oxazol-2-yl 151 —C(O)CH₂CH₂— phenylisoxazol-3-yl 152 —C(O)CH₂CH₂— 3-chlorophenyl methyl 153 —C(O)CH₂CH₂—3-chlorophenyl ethyl 154 —C(O)CH₂CH₂— 3-chlorophenyl phenyl 155—C(O)CH₂CH₂— 3-chlorophenyl thiophene- 2-yl 156 —C(O)CH₂CH₂—3-chlorophenyl thiazol-2-yl 157 —C(O)CH₂CH₂— 3-chlorophenyl oxazol-2-yl158 —C(O)CH₂CH₂— 3-chlorophenyl isoxazol-3-yl 159 —C(O)CH₂CH₂—3-methoxyphenyl methyl 160 —C(O)CH₂CH₂— 3-methoxyphenyl ethyl 161—C(O)CH₂CH₂— 3-methoxyphenyl phenyl 162 —C(O)CH₂CH₂— 3-methoxyphenylthiophene- 2-yl 163 —C(O)CH₂CH₂— 3-methoxyphenyl thiazol-2-yl 164—C(O)CH₂CH₂— 3-methoxyphenyl oxazol-2-yl 165 —C(O)CH₂CH₂—3-methoxyphenyl isoxazol-3-yl 166 —C(O)CH₂CH₂— 3-fluorophenyl methyl 167—C(O)CH₂CH₂— 3-fluorophenyl ethyl 168 —C(O)CH₂CH₂— 3-fluorophenyl phenyl169 —C(O)CH₂CH₂— 3-fluorophenyl thiophene- 2-yl 170 —C(O)CH₂CH₂—3-fluorophenyl thiazol-2-yl 171 —C(O)CH₂CH₂— 3-fluorophenyl oxazol-2-yl172 —C(O)CH₂CH₂— 3-fluorophenyl isoxazol-3-yl 173 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl methyl 174 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl ethyl 175 —C(O)CH₂CH₂— 2,5-dimethylthiazol-4-ylphenyl 176 —C(O)CH₂CH₂— 2,5-dimethylthiazol-4-yl thiophene- 2-yl 177—C(O)CH₂CH₂— 2,5-dimethylthiazol-4-yl thiazol-2-yl 178 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl oxazol-2-yl 179 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl isoxazol-3-yl 180 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl methyl 181 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl ethyl 182 —C(O)CH₂CH₂— 2,4-dimethylthiazol-5-ylphenyl 183 —C(O)CH₂CH₂— 2,4-dimethylthiazol-5-yl thiophene- 2-yl 184—C(O)CH₂CH₂— 2,4-dimethylthiazol-5-yl thiazol-2-yl 185 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl oxazol-2-yl 186 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl isoxazol-3-yl 187 —C(O)CH₂CH₂—4-ethylthiazol-2-yl methyl 188 —C(O)CH₂CH₂— 4-ethylthiazol-2-yl ethyl189 —C(O)CH₂CH₂— 4-ethylthiazol-2-yl phenyl 190 —C(O)CH₂CH₂—4-ethylthiazol-2-yl thiophene- 2-yl 191 —C(O)CH₂CH₂— 4-ethylthiazol-2-ylthiazol-2-yl 192 —C(O)CH₂CH₂— 4-ethylthiazol-2-yl oxazol-2-yl 193—C(O)CH₂CH₂— 4-ethylthiazol-2-yl isoxazol-3-yl 194 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl methyl 195 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl ethyl 196 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl phenyl 197 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiophene- 2-yl 198 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl 199 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl 200 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl

The compounds encompassed within the second aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeII and described in Example 2 herein below.

Example 24-((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid (10)

Preparation of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamicacid tert-butyl ester (6): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g,4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). Thereaction mixture is stirred at 0° C. for 20 minutes and filtered. Thefiltrate is treated with an ether solution of diazomethane (−16 mmol) at0° C. The reaction mixture is stirred at room temperature for 3 hoursthen concentrated in vacuo. The resulting residue is dissolved in EtOAcand washed successively with water and brine, dried (Na₂SO₄), filteredand concentrated. The residue is purified over silica (hexane/EtOAc 2:1)to afford 1.1 g (82% yield) of the desired product as a slightly yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd,J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).

Preparation of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate (7): To a 0° C.solution of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is addeddropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture isstirred at 0° C. for 1.5 hours then the reaction is quenched at 0° C.with sat. Na₂CO₃. The mixture is extracted with EtOAc (3×25 mL) and thecombined organic extracts are washed with brine, dried (Na₂SO₄),filtered and concentrated to obtain 0.400 g of the product which is usedin the next step without further purification. ¹H NMR (300 MHz, CDCl₃) δ8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H),4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of(S)-2-(4-nitrophenyl)-1-[(thiophene-2-yl)thiazol-4-yl]ethanaminehydrobromide salt (8): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (7.74 g, 20mmol), and thiophene-2-carbothioic acid amide (3.14 g, 22 mmol) in CH₃CN(200 mL) is refluxed for 5 hours. The reaction mixture is cooled to roomtemperature and diethyl ether (50 mL) is added to the solution. Theprecipitate which forms is collected by filtration. The solid is driedunder vacuum to afford 7.14 g (87% yield) of the desired product. ESI+MS332 (M+1).

Preparation of2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}acetamide(9): To a solution of2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8, (0.41 g,1 mmol) 3-chlorophenylacetic acid (0.170 g, 1 mmol) and1-hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 mL) at 0°,is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190 g,1 mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.290 g (60% yield) of the desired product which isused without further purification. ESI− MS 482 (M−1).

Preparation of{4-[2-(3-chlorophenyl)acetylamino]-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (10):2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene2-yl)thiazol-4-yl]ethyl}acetamide,9, (0.290 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.157 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.078 g of the desired product as the ammoniumsalt. ¹H NMR (CD3OD) δ 7.61 (d, 1H, J=3.6 Hz), 7.58 (d, 1H, J=5.1 Hz),7.41-7.35 (m, 1H), 7.28-7.22 (m, 2H), 7.18-6.98 (m, 6H), 5.33 (t, 1H,J=6.6 Hz), 3.70 (d, 2H, J=3.9 Hz), 3.23 (1H, A of ABX, J=6.6, 13.8 Hz),3.07 (1H, B of ABX, J=8.1, 13.5 Hz).

The following are non-limiting examples of compounds encompassed withinthe second aspect of Category I of the present disclosure.

4-((S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.35 (d, 1H, J=8.7 Hz), 7.61-7.57 (m, 2H),7.25-7.20 (m, 2H), 7.25-7.20 (m, 2H), 7.09 (s, 1H), 7.05 (d, 2H, J=4.2Hz), 6.99 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=7.8 Hz), 6.77 (s, 1H),5.30-5.28 (m, 1H), 3.76 (s, 3H), 3.51 (s, 2H), 3.20 (1H, A of ABX,J=6.3, 13.6 Hz), 3.06 (1H, B of ABX, J=8.1, 13.8 Hz).

4-{(S)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 8.30 (d, 1H, J=9 Hz), 7.61-7.56 (m, 2H),7.26-7.14 (m, 7H), 7.12 (d, 1H, J=1.5 Hz), 7.09 (d, 1H, J=2.1 Hz), 6.89(s, 1H), 5.28-5.26 (m, 1H), 3.18 (1H, A of ABX, J=6.2, 13.8 Hz), 2.96(1H, B of ABX, J=8.4, 13.6 Hz).

4-{(S)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.61-7.56 (m, 3H), 7.22-7.14 (m, 6H), 7.08 (d,1H), 7.00 (d, 1H, J=77.5 Hz), 6.870 (s, 1H), 5.25 (t, 1H, J=7.8 Hz),3.18 (1H, A of ABX, J=6.6, 13.8 Hz), 2.97 (1H, B of ABX, J=7.8, 13.8Hz), 2.87 (t, 2H, J=7.5 Hz), 2.51 (t, 2H, J=7.2 Hz).

4-{(S)-2-[2-(3-Fluorophenyl)acetamido]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.61-7.57 (m, 2H), 7.32-7.28 (m, 1H), 7.19-7.16(m, 2H), 7.08 (t, 1H, J=4.5 Hz), 7.02-6.95 (m, 6H), 5.29 (t, 1H, J=8.1Hz), 3.53 (s, 2H), 3.22 (1H, A of ABX, J=6.6, 13.9 Hz), 3.06 (1H, B ofABX, J=8.4, 13.6 Hz).

(S)-4-{2-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)acetamido]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.98-7.95 (m, 2H), 7.48-7.46 (m, 3H), 7.23 (s, 1H),7.09-7.05 (m, 4H), 5.33 (t, 1H, J=7.2 Hz), 3.33-3.06 (m, 2H), 2.35 (s,3H).

4-{(S)-2-[2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.62 (d, 1H, J=3 Hz), 7.58 (d, 1H, J=15.6 Hz),7.27 (s, 1H), 7.16 (t, 1H, J=1.5 Hz), 5.42-5.32 (m, 1H), 4.31 (d, 1H,J=15.6 Hz), 3.91 (d, 1H, J=15.9 Hz), 3.60-3.50 (m, 4H), 3.30-3.23 (m,2H), 2.98 (1H, B of ABX, J=9.9, 13.8 Hz), 1.21 (t, 3H, J=6.9 Hz).

The third aspect of Category I of the present disclosure relates tocompounds having the formula:

wherein the linking unit L comprises a phenyl unit, said linking grouphaving the formula:—C(O)[(CR^(6a)H)][(CH₂)]—R^(5a) is phenyl or substituted phenyl and non-limiting examples of theunits R², R³, and R^(6a) are further exemplified herein below in TableIII.

TABLE III No. R² R³ R^(6a) 201 methyl hydrogen phenyl 202 methylhydrogen 2-fluorophenyl 203 methyl hydrogen 3-fluorophenyl 204 methylhydrogen 4-fluorophenyl 205 methyl hydrogen 3,4-difluorophenyl 206methyl hydrogen 2-chlorophenyl 207 methyl hydrogen 3-chlorophenyl 208methyl hydrogen 4-chlorophenyl 209 methyl hydrogen 3,4-dichlorophenyl210 methyl hydrogen 2-methoxyphenyl 211 methyl hydrogen 3-methoxyphenyl212 methyl hydrogen 4-methoxyphenyl 213 ethyl hydrogen phenyl 214 ethylhydrogen 2-fluorophenyl 215 ethyl hydrogen 3-fluorophenyl 216 ethylhydrogen 4-fluorophenyl 217 ethyl hydrogen 3,4-difluorophenyl 218 ethylhydrogen 2-chlorophenyl 219 ethyl hydrogen 3-chlorophenyl 220 ethylhydrogen 4-chlorophenyl 221 ethyl hydrogen 3,4-dichlorophenyl 222 ethylhydrogen 2-methoxyphenyl 223 ethyl hydrogen 3-methoxyphenyl 224 ethylhydrogen 4-methoxyphenyl

The compounds encompassed within the third aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeIII and described in Example 3 herein below.

Example 3(S)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid (12)

Preparation of(S)—N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide(11): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60 g, 2.65 mmol) and1-hydroxybenzotriazole (HOBt) (0.180 g, 1.33 mmol) in DMF (10 mL) at 0°,is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.502 g,2.62 mmol) followed by triethylamine (1.1 mL, 7.95 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.903 g (70% yield) of the desired product which isused without further purification.

Preparation of(S)-4-(2-(2,3-diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (12)(S)—N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide,11, (0.903 g) is dissolved in MeOH (10 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (30 mL) and treated with SO₃-pyridine(0.621 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.415 g of the desired product as the ammoniumsalt. ¹H NMR (CD3OD) δ 8.59-8.52 (m, 1H), 7.37-7.04 (m, 9H), 6.97-6.93(m, 1H), 6.89-6.85 (m, 2H), 5.36-5.32 (m, 1H), 3.91-3.83 (m, 1H), 3.29(1H, A of ABX, obscured by solvent), 3.15 (1H, B of ABX, J=5.4, 33.8Hz), 2.99-2.88 (m, 2H), 2.81-2.69 (m, 2H), 1.32-1.25 (m, 3H).

The precursors of many of the Z units which comprise the third aspect ofCategory I are not readily available. The following procedureillustrates an example of the procedure which can be used to providedifferent R^(6a) units according to the present disclosure. Using theprocedure outlined in Scheme IV and described in Example 4 the artisancan make modifications without undue experimentation to achieve theR^(5a) units encompassed by the present disclosure.

Example 4 2-(2-Methoxyphenyl)-3-phenylpropanoic acid (14)

Preparation of methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (13): A 500mL round-bottom flask is charged with methyl 2-(2-methoxyphenyl)acetate(8.496 g, 47 mmol, 1 eq) and THF (200 mL). The homogeneous mixture iscooled to 0° C. in an ice bath. Lithium diisopropyl amide (23.5 mL of a2.0M solution in heptane/THF) is added, maintaining a temperature lessthan 3° C. The reaction is stirred 45 minutes at this reducedtemperature. Benzyl bromide (5.6 mL, 47 mmol, 1 eq) is added dropwise.The reaction is allowed to gradually warm to room temperature and isstirred for 18 hours. The reaction is quenched with 1N HCl and extracted3 times with equal portions of EtOAc. The combined extracts are washedwith H₂O and brine, dried over Na₂SO₄, filtered, and concentrated. Theresidue is purified over silica to afford 4.433 g (35%) of the desiredcompound. ESI+MS 293 (M+Na).

Preparation of 2-(2-methoxyphenyl)-3-phenylpropanoic acid (14): Methyl2-(2-methoxyphenyl)-3-phenylpropanoate (4.433 g, 16 mmol, 1 eq) isdissolved in 100 mL of a 1:1 (v:v) mixture of THF and methanol. Sodiumhydroxide (3.28 g, 82 mmol, 5 eq) is added and the reaction mixture isstirred 18 hours at room temperature. The reaction is then poured intoH₂O and the pH is adjusted to 2 via addition of 1N HCl. A whiteprecipitate forms which is removed by filtration. The resulting solutionis extracted with 3 portion of diethyl ether. The extracts are pooled,washed with H₂O and brine, dried over Na₂SO₄, filtered, and concentratedin vacuo. The resulting residue is purified over silica to afford 2.107g (51%) of the desired compound. ESI− MS 255 (M−1), 211 (M—CO₂H).

Intermediate 14 can be carried forward according to the procedureoutlined in Scheme III and described in Example 3 to produce thefollowing compound according to the third aspect of Category I.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.32-7.12 (m, 7H), 7.05-7.02 (m, 1H), 6.99-6.83(m, 4H), 6.80-6.75 (m, 2H), 5.35-5.31 (m, 1H), 4.31-4.26 (m, 1H), 3.75(s, 3H), 3.20-2.90 (m, 4H), 2.79-2.74 (m, 2H), 1.32-1.25 (m, 3H).

The following are further non-limiting examples of compounds accordingto the third aspect of Category I of the present disclosure.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.33-6.87 (m, 14H), 5.39-5.25 (m, 1H), 3.95-3.83(m, 1H), 3.31-3.10 (m, 1H), 3.05-2.88 (m, 2H), 2.80-2.70 (m, 2H),1.32-1.23 (m, 3H). ¹⁹F NMR δ 47.59.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.85 (d, 1H, J=8.4 Hz), 7.25-7.20 (m, 1H),7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m, 2H), 5.45-5.40 (m, 1H),4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m, 2H), 1.10 (s, 9H).

The fourth aspect of Category I of the present disclosure relates tocompounds having the formula:

wherein the linking unit L comprises a phenyl unit, said linking grouphaving the formula:—C(O)[(CR^(6a)H)][(CH₂]R^(5a) is substituted or unsubstituted heteroaryl and the units R², R³,and R^(5a) are further exemplified herein below in Table IV.

TABLE IV No. R² R³ R^(6a) 225 methyl hydrogen3-methyl-1,2,4-oxadiazol-5-yl 226 methyl hydrogen thiophene-2-yl 227methyl hydrogen thiazol-2-yl 228 methyl hydrogen oxazol-2-yl 229 methylhydrogen isoxazol-3-yl 230 ethyl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl231 ethyl hydrogen thiophene-2-yl 232 ethyl hydrogen thiazol-2-yl 233ethyl hydrogen oxazol-2-yl 234 ethyl hydrogen isoxazol-3-yl 235 ethylmethyl 3-methyl-1,2,4-oxadiazol-5-yl 236 ethyl methyl thiophene-2-yl 237ethyl methyl thiazol-2-yl 238 ethyl methyl oxazol-2-yl 239 ethyl methylisoxazol-3-yl 240 thiophene-2-yl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl241 thiophene-2-yl hydrogen thiophene-2-yl 242 thiophene-2-yl hydrogenthiazol-2-yl 243 thiophene-2-yl hydrogen oxazol-2-yl 244 thiophene-2-ylhydrogen isoxazol-3-yl 245 isoxazol-3-yl hydrogen3-methyl-1,2,4-oxadiazol-5-yl 246 isoxazol-3-yl hydrogen thiophene-2-yl247 isoxazol-3-yl hydrogen thiazol-2-yl 248 isoxazol-3-yl hydrogenoxazol-2-yl 249 isoxazol-3-yl hydrogen isoxazol-3-yl

The compounds encompassed within the fourth aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in Scheme Vand described in Example 5 herein below.

Example 54-{(S)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (17)

Preparation ofethyl-2-benzyl-3-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)-ethylamino]-3-oxopropanoate(15): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3-oxopropanoic acid (0.277 g)and 1-hydroxybenzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF (10 mL) at0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.240g, 1.25 mmol) followed by diisopropylethylamine (DIPEA) (0.306 g). Themixture is stirred at 0° C. for 30 minutes then at room temperatureovernight. The reaction mixture is diluted with water and extracted withEtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5%aqueous NaHCO₃, water and brine, and dried over Na₂SO₄. The solvent isremoved in vacuo to afford 0.169 g (31% yield) of the desired productwhich is used without further purification.

Preparation ofN-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide(16): Ethyl2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoateis dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate(80 mg) and acetamide oxime (43 mg) are added and treated with 80 mgpotassium carbonate and 43 mg acetamide oxime at reflux. The reactionmixture is cooled to room temperature, filtered and concentrated. Theresidue is chromatographed over silica to afford 0.221 g (94%) of thedesired product as a yellow oil.

Preparation of4-{(S)-2-(4-ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (17):N-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide,16, (0.221 g) and tin (II) chloride (507 mg, 2.2 mmol) are dissolved inEtOH (25 mL) and the solution is brought to reflux 4 hours. The solventis removed in vacuo and the resulting residue is dissolved in EtOAc. Asaturated solution of NaHCO₃ (50 mL) is added and the solution isstirred 1 hour. The organic layer is separated and the aqueous layerextracted twice with EtOAc. The combined organic layers are dried(Na₂SO₄), filtered and concentrated to a residue which is dissolved inpyridine (0.143 g) and treated with SO₃-pyridine (0.143 g). The reactionis stirred at room temperature for 5 minutes after which a 7% solutionof NH₄OH is added. The mixture is then concentrated and the resultingresidue is purified by reverse phase chromatography to afford 0.071 g ofthe desired product as the ammonium salt. ¹H(CD₃OD): δ 7.29-6.87 (m,10H), 5.38-5.30 (m, 1H), 4.37-4.30 (m, 1H), 3.42-2.74 (m, 6H), 2.38-2.33(m, 3H), 1.34-1.28 (m, 3H).

Category II of the present disclosure relates to 2-(thiazol-2-yl)compounds having the formula:

wherein R¹, R², R³, and L are further defined herein in Table V hereinbelow.

TABLE V No. R² R³ R¹ 250 ethyl hydrogen thiophene-2-yl 251 ethylhydrogen thiazol-2-yl 252 ethyl hydrogen oxazol-2-yl 253 ethyl hydrogenisoxazol-3-yl 254 ethyl hydrogen thiophene-2-yl 255 ethyl hydrogenthiazol-2-yl 256 ethyl hydrogen oxazol-2-yl 257 ethyl hydrogenisoxazol-3-yl 258 ethyl hydrogen thiophene-2-yl 259 ethyl hydrogenthiazol-2-yl 260 ethyl methyl methyl 261 ethyl methyl ethyl 262 ethylmethyl propyl 263 ethyl methyl iso-propyl 264 ethyl methyl butyl 265ethyl methyl phenyl 266 ethyl methyl benzyl 267 ethyl methyl2-fluorophenyl 268 ethyl methyl 3-fluorophenyl 269 ethyl methyl4-fluorophenyl 270 phenyl hydrogen methyl 271 phenyl hydrogen ethyl 272phenyl hydrogen propyl 273 phenyl hydrogen iso-propyl 274 phenylhydrogen butyl 275 phenyl hydrogen phenyl 276 phenyl hydrogen benzyl 277phenyl hydrogen 2-fluorophenyl 278 phenyl hydrogen 3-fluorophenyl 279phenyl hydrogen 4-fluorophenyl 280 thiophene-2-yl hydrogen methyl 281thiophene-2-yl hydrogen ethyl 282 thiophene-2-yl hydrogen propyl 283thiophene-2-yl hydrogen iso-propyl 284 thiophene-2-yl hydrogen butyl 285thiophene-2-yl hydrogen phenyl 286 thiophene-2-yl hydrogen benzyl 287thiophene-2-yl hydrogen 2-fluorophenyl 288 thiophene-2-yl hydrogen3-fluorophenyl 289 thiophene-2-yl hydrogen 4-fluorophenyl

The compounds encompassed within Category II of the present disclosurecan be prepared by the procedure outlined in Scheme VI and described inExample 6 herein below.

Example 6(S)-4-[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)ethyl]-phenylsulfamicacid (19)

Preparation of(S)-N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-4-oxo-4-phenylbutanamide(18): 3-Benzoylpropionic acid (0.250 g) is dissolved in CH₂Cl₂ (5 mL),N-methyl imidazole (0.333 mL) is added and the resulting solution iscooled to 0° C. after which a solution of p-toluenesulfonyl chloride(0.320 g) in CH₂Cl₂ (2 mL) is added dropwise. After 0.5 hours(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) isadded. The reaction is stirred for 18 hours at room temperature and thenconcentrated in vacuo. The resulting residue is dissolved in EtOAc andwashed with 1N HCl and brine. The solution is dried over Na₂SO₄,filtered, and concentrated and the crude material purified over silicato afford 0.415 g of the desired product.

Preparation of(S)-4-[2-(4-ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)-ethyl]phenylsulfamicacid (19):(S)—N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide,18, (0.2 g) is dissolved in MeOH (15 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (5 mL) and treated with SO₃-pyridine(0.153 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.090 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD) δ 8.68 (d, 1H, J=8.2 Hz), 8.00 (d, 2H, J=7.2 Hz),7.80-7.50 (m, 3H), 7.12 (s, 4H), 7.03 (s, 1H), 5.46-5.38 (m, 1H),3.29-3.14 (m, 2H), 3.06-2.99 (m, 2H), 2.83 (q, 2H, J=7.5 Hz), 2.69-2.54(m, 2H), 1.33 (t, 3H, J=7.5 Hz).

The following are non-limiting examples of compounds encompassed withinCategory II of the present disclosure. The intermediate nitro compoundsof the following can be prepared by coupling the appropriate4-oxo-carboxcylic acid with intermediate 3 under the conditionsdescribed herein above for the formation of intermediate 4 of scheme I.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 8.59 (d, 1H, J=8.1 Hz), 7.14 (s, 4H), 7.08 (t,1H, J=13.0 Hz), 5.40-5.35 (m, 1H), 3.37-3.27 (m, 2H), 3.04-2.97 (m, 1H),2.83-2.61 (m, 4H), 2.54-2.36 (m, 3H), 1.33 (t, 2H, J=7.3 Hz), 1.09 (dd,6H, J=7.0, 2.2 Hz).

(S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.64 (d, 1H, J=8.4 Hz), 7.60 (d, 2H, J=10.6 Hz),7.11 (s, 3H), 7.04 (d, 2H, J=5.5 Hz), 5.42-5.40 (m, 1H), 4.30-4.22 (m,4H), 3.20-2.98 (m, 4H), 2.82 (q, 2H, J=7.3 Hz), 2.67-2.48 (m, 2H), 2.23(t, 2H, J=5.5 Hz), 1.32 (t, 3H, J=7.3 Hz).

(S)-4-{2-[4-(2,3-Dimethoxyphenyl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD), δ 8.64 (d, 1H, J=8.1 Hz), 7.21-7.11 (m, 7H), 7.02(s, 1H), 5.42 (q, 1H, J=5.9 Hz), 3.90 (d, 3H, J=3.3 Hz), 3.88 (d, 3H,J=2.9 Hz), 3.22-3.18 (m, 2H), 3.07-2.99 (m, 2H), 2.83 (q, 2H, J=7.3 Hz),2.63-2.54 (m, 2H), 1.34 (t, 3H, J=7.69 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.60 (d, 1H, J=12.8 Hz), 7.91-7.81 (m, 2H),7.48-7.44 (m, 1H), 7.22-7.21 (m, 1H), 6.99 (s, 3H), 6.91 (s, 1H), 5.30(q, 1H, J=5.4 Hz), 3.36 (q, 2H, J=7.0 Hz), 3.21-3.15 (m, 1H), 2.91-2.85(m, 1H), 2.74 (q, 2H, J=10.4 Hz), 2.57-2.50 (m, 2H), 1.20 (t, 3H, J=7.5Hz).

(S)-4-{2-[4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.52-7.47 (m, 2H), 7.11 (s, 4H), 7.03 (s, 1H),6.95 (d, 1H, J=8.4 Hz), 5.41 (q, 1H, J=3.7 Hz), 4.31 (d, 4H, J=5.5 Hz),3.24-3.12 (m, 2H), 3.06-2.98 (m, 2H), 2.83 (q, 2H, J=7.3 Hz), 2.62-2.53(m, 2H), 1.33 (t, 3H, J=7.3 Hz).

(S)-4-[2-(4-tert-butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenyl-sulfamicacid: ¹H NMR (CD₃OD), δ 7.10 (s 4H), 7.02 (s, 1H), 5.41 (q, 1H, J=3.7Hz), 3.30-3.25 (m, 1H), 3.06-2.99 (m, 1H), 2.83 (q, 2H, J=7.3 Hz),2.52-2.40 (m, 4H), 1.42 (s, 9H), 1.33 (t, 3H, J=7.3 Hz).

(S)-4-[2-(4-ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.62 (d, 1H, J=8.4 Hz), 7.10 (s, 4H), 7.02 (s,1H), 5.40 (q, 1H, 3.7 Hz), 4.15 (q, 2H, J=7.3 Hz), 3.28-3.25 (m, 1H),3.05-3.02 (m, 1H), 2.82 (q, 2H, J=4.4 Hz), 2.54-2.48 (m, 2H), 1.33 (t,3H, J=7.3 Hz), 1.24 (t, 3H, J=7.0 Hz).

The first aspect of Category III of the present disclosure relates to2-(thiazol-2-yl) compounds having the formula:

wherein non-limiting examples of R¹, R², and R³ are further describedherein below in Table VI.

TABLE VI No. R² R³ R¹ 290 methyl hydrogen phenyl 291 methyl hydrogenbenzyl 292 methyl hydrogen 2-fluorophenyl 293 methyl hydrogen3-fluorophenyl 294 methyl hydrogen 4-fluorophenyl 295 methyl hydrogen2-chlorophenyl 296 methyl hydrogen 3-chlorophenyl 297 methyl hydrogen4-chlorophenyl 298 ethyl hydrogen phenyl 299 ethyl hydrogen benzyl 300ethyl hydrogen 2-fluorophenyl 301 ethyl hydrogen 3-fluorophenyl 302ethyl hydrogen 4-fluorophenyl 303 ethyl hydrogen 2-chlorophenyl 304ethyl hydrogen 3-chlorophenyl 305 ethyl hydrogen 4-chlorophenyl 306thiene-2-yl hydrogen phenyl 307 thiene-2-yl hydrogen benzyl 308thiene-2-yl hydrogen 2-fluorophenyl 309 thiene-2-yl hydrogen3-fluorophenyl 310 thiene-2-yl hydrogen 4-fluorophenyl 311 thiene-2-ylhydrogen 2-chlorophenyl 312 thiene-2-yl hydrogen 3-chlorophenyl 313thiene-2-yl hydrogen 4-chlorophenyl

The compounds encompassed within Category III of the present disclosurecan be prepared by the procedure outlined in Scheme VIII and describedin Example 7 herein below.

Example 7(S)-4-(2-(3-Benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (21)

Preparation of(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea(20): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.360 g, 1 mmol) and Et₃N (0.42 mL, 3 mmol) in 10 mL CH₂Cl₂ is addedbenzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at roomtemperature for 18 hours. The product is isolated by filtration toafford 0.425 g (96% yield) of the desired product which is used withoutfurther purification.

Preparation of(S)-4-(2-(3-benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid (21):(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea, 20,(0.425 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10%w/w) is added and the mixture is stirred under a hydrogen atmosphere 18hours. The reaction mixture is filtered through a bed of CELITE™ and thesolvent is removed under reduced pressure. The crude product isdissolved in pyridine (12 mL) and treated with SO₃-pyridine (0.220 g).The reaction is stirred at room temperature for 5 minutes after which a7% solution of NH₄OH is added. The mixture is then concentrated and theresulting residue is purified by reverse phase chromatography to afford0.143 g of the desired product as the ammonium salt. ¹H NMR (CD₃OD) δ7.32-7.30 (m, 2H), 7.29-7.22 (m, 3H), 7.12-7.00 (m, 4H), 6.84 (d, 1H,J=8.1 Hz), 5.35-5.30 (m, 1H), 4.29 (s, 2H), 3.27-3.22 (m, 3H), 3.11-3.04(m, 3H), 2.81 (q, 2H, J=10.2, 13.0 Hz), 1.31 (t, 3H, J=4.5 Hz).

The following is a non-limiting examples of compounds encompassed withinthe first aspect of Category III of the present disclosure.

4-{[(S)-2-(2-Ethylthiazol-4-yl)-2-(3-(R)-methoxy-1-oxo-3-phenylpropan-2-yl)ureido]ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.36-7.26 (m, 3H), 7.19-7.17 (m, 2H), 7.10-7.06(m, 2H), 6.90-6.86 (m, 3H), 5.12-5.06 (m, 1H), 4.60-4.55 (m, 1H), 3.69(s, 3H) 3.12-2.98 (m, 6H), 1.44-1.38 (m, 3H).

The second aspect of Category III of the present disclosure relates to2-(thiazol-4-yl) compounds having the formula:

wherein non-limiting examples of R¹ and R⁴ are further described hereinbelow in Table VII.

TABLE VII No. R¹ R⁴ 314 methyl methyl 315 ethyl methyl 316 n-propylmethyl 317 iso-propyl methyl 318 phenyl methyl 319 benzyl methyl 3202-fluorophenyl methyl 321 2-chlorophenyl methyl 322 thiophene-2-ylmethyl 323 thiazol-2-yl methyl 324 oxazol-2-yl methyl 325 isoxazol-3-ylmethyl 326 methyl ethyl 327 ethyl ethyl 328 n-propyl ethyl 329iso-propyl ethyl 330 phenyl ethyl 331 benzyl ethyl 332 2-fluorophenylethyl 333 2-chlorophenyl ethyl 334 thiophene-2-yl ethyl 335 thiazol-2-ylethyl 336 oxazol-2-yl ethyl 337 isoxazol-3-yl ethyl 338 methylthiophene-2-yl 339 ethyl thiophene-2-yl 340 n-propyl thiophene-2-yl 341iso-propyl thiophene-2-yl 342 phenyl thiophene-2-yl 343 benzylthiophene-2-yl 344 2-fluorophenyl thiophene-2-yl 345 2-chlorophenylthiophene-2-yl 346 thiophene-2-yl thiophene-2-yl 347 thiazol-2-ylthiophene-2-yl 348 oxazol-2-yl thiophene-2-yl 349 isoxazol-3-ylthiophene-2-yl 350 methyl thiazol-2-yl 351 ethyl thiazol-2-yl 352n-propyl thiazol-2-yl 353 iso-propyl thiazol-2-yl 354 phenylthiazol-2-yl 355 benzyl thiazol-2-yl 356 2-fluorophenyl thiazol-2-yl 3572-chlorophenyl thiazol-2-yl 358 thiophene-2-yl thiazol-2-yl 359thiazol-2-yl thiazol-2-yl 360 oxazol-2-yl thiazol-2-yl 361 isoxazol-3-ylthiazol-2-yl 362 methyl oxazol-2-yl 363 ethyl oxazol-2-yl 364 n-propyloxazol-2-yl 365 iso-propyl oxazol-2-yl 366 phenyl oxazol-2-yl 367 benzyloxazol-2-yl 368 2-fluorophenyl oxazol-2-yl 369 2-chlorophenyloxazol-2-yl 370 thiophene-2-yl oxazol-2-yl 371 thiazol-2-yl oxazol-2-yl372 oxazol-2-yl oxazol-2-yl 373 isoxazol-3-yl oxazol-2-yl

The compounds encompassed within the second aspect of Category III ofthe present disclosure can be prepared by the procedure outlined inScheme VIII and described in Example 8 herein below.

Example 84-{(S)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid (23)

Preparation of1-benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}urea(22): To a solution of(S)-2-(4-nitrophenyl)-1-[(2-thiophene-2-yl)thiazol-4-yl)ethan-aminehydrobromide salt, 8, and Et₃N (0.42 mL, 3 mmol) in 10 mL DCM is addedbenzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at roomtemperature for 18 hours. The product is isolated by filtration toafford 0.445 g (96% yield) of the desired product which is used withoutfurther purification.

Preparation of4-{(S)-2-(3-benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid (23):1-Benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}urea,22, (0.445 g) is dissolved in MeOH (10 mL) and CH₂Cl₂ (5 mL). Acatalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 18 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.110 g). The reaction is stirred at room temperaturefor 5 minutes after which a 7% solution of NH₄OH is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 0.080 g of the desired product as theammonium salt. ¹H NMR (CD3OD) δ 7.61 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=6Hz), 7.33-7.22 (m, 4H), 7.17-7.14 (m, 1H), 7.09-6.94 (m, 6H), 5.16 (t,1H, J=6.6 Hz), 4.13 (s, 2H), 3.14-3.11 (m, 2H).

Category IV of the present disclosure relates to 2-(thiazol-4-yl)compounds having the formula:

wherein R¹, R⁴, and L are further defined herein in Table VIII hereinbelow.

TABLE VIII No. R⁴ L R¹ 374 methyl —SO₂— methyl 375 ethyl —SO₂— methyl376 phenyl —SO₂— methyl 377 thiophene-2-yl —SO₂— methyl 378 methyl —SO₂—trifluoromethyl 379 ethyl —SO₂— trifluoromethyl 380 phenyl —SO₂—trifluoromethyl 381 thiophene-2-yl —SO₂— trifluoromethyl 382 methyl—SO₂— ethyl 383 ethyl —SO₂— ethyl 384 phenyl —SO₂— ethyl 385thiophene-2-yl —SO₂— ethyl 386 methyl —SO₂— 2,2,2-trifluoroethyl 387ethyl —SO₂— 2,2,2-trifluoroethyl 388 phenyl —SO₂— 2,2,2-trifluoroethyl389 thiophene-2-yl —SO₂— 2,2,2-trifluoroethyl 390 methyl —SO₂— phenyl391 ethyl —SO₂— phenyl 392 phenyl —SO₂— phenyl 393 thiophene-2-yl —SO₂—phenyl 394 methyl —SO₂— 4-fluorophenyl 395 ethyl —SO₂— 4-fluorophenyl396 phenyl —SO₂— 4-fluorophenyl 397 thiophene-2-yl —SO₂— 4-fluorophenyl398 methyl —SO₂— 3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl 399 ethyl—SO₂— 3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl 400 phenyl —SO₂—3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl 401 thiophene-2-yl —SO₂—3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl 402 methyl —SO₂—1-methyl-1H-imidazol-4-yl 403 ethyl —SO₂— 1-methyl-1H-imidazol-4-yl 404phenyl —SO₂— 1-methyl-1H-imidazol-4-yl 405 thiophene-2-yl —SO₂—1-methyl-1H-imidazol-4-yl 406 methyl —SO₂— 4-acetamidophenyl 407 ethyl—SO₂— 4-acetamidophenyl 408 phenyl —SO₂— 4-acetamidophenyl 409thiophene-2-yl —SO₂— 4-acetamidophenyl 410 methyl —SO₂CH₂— phenyl 411ethyl —SO₂CH₂— phenyl 412 phenyl —SO₂CH₂— phenyl 413 thiophene-2-yl—SO₂CH₂— phenyl 414 methyl —SO₂CH₂— (4- methylcarboxyphenyl)methyl 415ethyl —SO₂CH₂— (4- methylcarboxyphenyl)methyl 416 phenyl —SO₂CH₂— (4-methylcarboxyphenyl)methyl 417 thiophene-2-yl —SO₂CH₂— (4-methylcarboxyphenyl)methyl 418 methyl —SO₂CH₂—(2-methylthiazol-4-yl)methyl 419 ethyl —SO₂CH₂—(2-methylthiazol-4-yl)methyl 420 phenyl —SO₂CH₂—(2-methylthiazol-4-yl)methyl 421 thiophene-2-yl —SO₂CH₂—(2-methylthiazol-4-yl)methyl 422 methyl —SO₂CH₂CH₂— phenyl 423 ethyl—SO₂CH₂CH₂— phenyl 424 phenyl —SO₂CH₂CH₂— phenyl 425 thiophene-2-yl—SO₂CH₂CH₂— phenyl

The compounds encompassed within Category IV of the present disclosurecan be prepared by the procedure outlined in Scheme IX and described inExample 9 herein below.

Example 9{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (25)

Preparation of(S)—N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-phenylmethanesulfonamide(24): To a suspension of2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8, (330 mg,0.80 mmol) in CH₂Cl₂ (6 mL) at 0° C. is added diisopropylethylamine(0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg,0.88 mmol). The reaction mixture is stirred at room temperature for 14hours. The mixture is diluted with CH₂Cl₂ and washed with sat. NaHCO₃followed by brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting residue is purified over silica to afford 210 mg of thedesired product as a white solid.

Preparation of{4-(S)-[2-phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (25):(S)—N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-phenylmethanesulfonamide,24, (210 mg, 0.41 mmol) is dissolved in MeOH (4 mL). A catalytic amountof Pd/C (10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(197 mg, 1.23 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.060 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.52-7.63 (m, 6.70-7.28 (m, 11H), 4.75(t, J=7.2 Hz, 1H), 3.95-4.09 (m, 2H), 3.20 (dd, J=13.5 and 7.8 Hz, 1H),3.05 (dd, J=13.5 and 7.8 Hz, 1H). 1013770

Intermediates for use in Step (a) of Scheme IX can be convenientlyprepared by the procedure outlined herein below in Scheme X anddescribed in Example 10.

Example 10 (2-Methylthiazol-4-yl)methanesulfonyl chloride (27)

Preparation of sodium (2-methylthiazol-4-yl)methanesulfonate (26):4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H₂O(2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reactionmixture is subjected to microwave irradiation for 20 minutes at 200° C.The reaction mixture is diluted with H₂O (30 mL) and washed with EtOAc(2×25 mL). The aqueous layer is concentrated to afford 0.368 g of thedesired product as a yellow solid. LC/MS ESI+194 (M+1, free acid).

Preparation of (2-methylthiazol-4-yl)methanesulfonyl chloride (27):Sodium (2-methylthiazol-4-yl)methanesulfonate (357 mg, 1.66 mmol) isdissolved in phosphorous oxychloride (6 mL) and is treated withphosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture isstirred at 50° C. for 3 hours, then allowed to cool to room temperature.The solvent is removed under reduced pressure and the residue isre-dissolved in CH₂Cl₂ (40 mL) and is washed with sat. NaHCO₃ and brine.The organic layer is dried over MgSO₄, filtered, and the solvent removedin vacuo to afford 0.095 g of the desired product as a brown oil. LC/MSESI+211 (M+1). Intermediates are obtained in sufficient purity to becarried forward according to Scheme IX without the need for furtherpurification.

4-{(S)-2-[(2-methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.71-7.66 (m, 2H), 7.27-7.10 (m, 7H), 4.87 (t, 1H,J=7.3 Hz), 4.30-4.16 (q, 2H, J=13.2 Hz), 3.34-3.13 (m, 2H), 2.70 (s,3H).

The following are non-limiting examples of compounds encompassed withinCategory IV of the present disclosure.

{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.27-7.32 (m, 3H), 7.16-7.20 (m, 3H),7.05-7.6 (m, 2H), 6.96 (d, J=8.4 Hz, 2H), 4.70 (t, J=9.0 Hz, 1H),3.91-4.02 (m, 2H), 2.95-3.18 (m, 4H), 1.41 (t, J=7.5 Hz, 3H).

{4-(S)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.20 (t, J=8.1 Hz. 1H), 6.94-7.08 (m,4H), 6.88-6.94 (m, 3H), 6.75-6.80 (m, 1H), 4.67 (t, J=7.2 Hz, 1H),3.90-4.0 (m, 2H), 3.76 (s, 3H), 2.95-3.16 (m, 4H), 1.40 (t, J=7.5 HZ,3H).

(S)-4-{[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]methyl}-benzoicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 7.90-7.94 (m, 2H),7.27-7.30 (m, 2H), 7.06-7.11 (m, 3H), 6.97-7.00 (m, 2H), 4.71 (t, J=7.2Hz, 1H), 3.95-4.08 (4, 2H), 3.92 (s, 3H), 2.80-3.50 (m, 4H), 1.38-1.44(m, 3H).

(S)-4-[2-(2-Ethylthiazol-4-yl)-2-(1-methyl-1H-imidazol-4-sulfonamido)ethyl]-phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.54 (s, 1H, 7.20 (s, 1H), 7.09 (s,1H), 6.92-7.00 (m, 4H), 4.62 (t, J=5.4 Hz, 1H), 3.70 (s, 3H), 2.98-3.14(m, 3H), 2.79 (dd, J=9.3 and 15.0 Hz, 1H), 1.39 (q, J=7.5 Hz, 3H).

4-{(S)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(2,2,2-trifluoroethylsulfonamido)-ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.62-7.56 (m, 2H), 7.22 (s, 1H), 7.16-7.06 (m, 5H),4.84 (t, 1H, J=7.6 Hz), 3.71-3.62 (m, 2H), 3.32-3.03 (m, 2H).

{4-(S)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.56-7.62 (m, 2H), 7.04-7.19 (m, 9H),6.94-6.97 (m, 2H), 4.78 (t, J=7.8 Hz, 1H), 3.22-3.30 (m, 2H)), 3.11 (dd,J=13.5 and 7.8 Hz, 1H), 2.78-2.87 (m, 4H).

{4-(S)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.56-7.62 (m, 2H), 6.99-7.17 (m, 10H),4.72 (t, J=7.8 Hz, 1H), 3.21 (dd, J=13.5 and 7.2 Hz, 1H), 3.02 (dd,J=13.5 and 7.2 Hz, 1H), 2.39-2.64 (m, 4H), 1.65-1.86 (m, 2H).

(S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonylamino)-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.53 (d, J=5.1 Hz, 1H) 7.48 (d, J=5.1Hz, 1H), 7.13-7.10 (m, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.93-6.88 (m, 3H),6.75 (d, J=8.1 Hz, 1H), 6.54 (d, J=8.1 Hz, 1H), 4.61 (t, J=7.5 Hz, 1H),4.20-4.08 (m, 2H), 3.14-3.00 (m, 4H), 2.69 (s, 3H).

4-{(S)-2-(4-acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.67-7.52 (m, 6H), 7.24-7.23 (m, 1H), 7.12-7.09 (m,3H), 7.02-6.99 (m, 2H), 4.70 (t, 1H, J=7.3 Hz), 3.25-3.00 (m, 2H), 2.24(s, 3H).

The first aspect of Category V of the present disclosure relates tocompounds having the formula:

wherein R¹ is a substituted or unsubstituted heteroaryl and R⁴ is C₁-C₆linear, branched, or cyclic alkyl as further described herein below inTable IX.

TABLE IX No. R⁴ R¹ 426 —CH₃ 4-(methoxycarbonyl)thiazol-5-yl 427 —CH₃4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 428 —CH₃5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 429 —CH₃5-(2-methoxyphenyl)oxazol-2-yl 430 —CH₃5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 431 —CH₃5-[4-(methylcarboxy)phenyl]oxazol-2-yl 432 —CH₃5-(3-methoxybenzyl)oxazol-2-yl 433 —CH₃ 5-(4-phenyl)oxazol-2-yl 434 —CH₃5-(2-methoxyphenyl)thiazol-2-yl 435 —CH₃ 5-(3-methoxyphenyl)thiazol-2-yl436 —CH₃ 5-(4-fluorophenyl)thiazol-2-yl 437 —CH₃5-(2,4-difluorophenyl)thiazol-2-yl 438 —CH₃5-(3-methoxybenzyl)thiazol-2-yl 439 —CH₃ 4-(3-methoxyphenyl)thiazol-2-yl440 —CH₃ 4-(4-fluorophenyl)thiazol-2-yl 441 —CH₂CH₃4-(methoxycarbonyl)thiazol-5-yl 442 —CH₂CH₃4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 443 —CH₂CH₃5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 444 —CH₂CH₃5-(2-methoxyphenyl)oxazol-2-yl 445 —CH₂CH₃5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 446 —CH₂CH₃5-[4-(methylcarboxy)phenyl]oxazol-2-yl 447 —CH₂CH₃5-(3-methoxybenzyl)oxazol-2-yl 448 —CH₂CH₃ 5-(4-phenyl)oxazol-2-yl 449—CH₂CH₃ 5-(2-methoxyphenyl)thiazol-2-yl 450 —CH₂CH₃5-(3-methoxyphenyl)thiazol-2-yl 451 —CH₂CH₃5-(4-fluorophenyl)thiazol-2-yl 452 —CH₂CH₃5-(2,4-difluorophenyl)thiazol-2-yl 453 —CH₂CH₃5-(3-methoxybenzyl)thiazol-2-yl 454 —CH₂CH₃4-(3-methoxyphenyl)thiazol-2-yl 455 —CH₂CH₃4-(4-fluorophenyl)thiazol-2-yl 456 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl 457 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 458 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl 459cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl 460 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 461cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl 462 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl 463 cyclopropyl 5-(4-phenyl)oxazol-2-yl464 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl 465 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl 466 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl 467 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl 468 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl 469 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl 470 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the first aspect of Category V which comprise asubstituted or unsubstituted thiazol-4-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XI and described herein below inExample 11.

Example 11(S)-4-(2-(2-Phenylthiazol-4-yl)-2-(4-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamicacid (31)

Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanaminehydrobromide salt (28): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (1.62 g, 4.17mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CH₃CN (5 mL) is refluxedfor 24 hours. The reaction mixture is cooled to room temperature anddiethyl ether (50 mL) is added to the solution. The precipitate whichforms is collected by filtration. The solid is dried under vacuum toafford 1.2 g (67% yield) of the desired product. LC/MS ESI+326 (M+1).

Preparation of(S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole (29):To a solution of(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromidesalt, 29, (726 mg, 1.79 mmol) and CaCO₃ (716 mg, 7.16 mmol) in H₂O (2mL) is added CCl₄ (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol).The reaction is stirred at room temperature for 18 hours then dilutedwith CH₂Cl₂ and water. The layers are separated and the aqueous layerextracted with CH₂Cl₂. The combined organic layers are washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to a residue which ispurified over silica (CH₂Cl₂) to afford 480 mg (73%) of the desiredproduct as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, J=8.7 Hz,2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15(d, J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H),3.46 (dd, J=13.8 and 6.0 Hz).

Preparation of (S)-methyl5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carboxylate(30): To a suspension of potassium tert-butoxide (89 mg, 0.75 mmol) inTHF (3 mL) is added methyl isocyanoacetate (65 μL, 0.68 mmol) followedby (S)-2-phenyl-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole, 29,(250 mg, 0.68 mmol). The reaction mixture is stirred at room temperaturefor 2 hours then poured into sat. NaHCO₃. The mixture is extracted withEtOAc (3×25 mL) and the combined organic layers are washed with brineand dried (Na₂SO₄) and concentrated in vacuo. The crude residue ispurified over silica to afford 323 mg (˜100% yield) of the desiredproduct as a slightly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.09-8.13(m, 2H), 7.95-7.98 (m, 3H), 7.84 (d, J=1.2 Hz, 1H), 7.44-7.50 (m, 3H),7.28-7.31 (m, 2H), 7.96 (d, J=0.6 Hz, 1H), 4.71-4.78 (m, 1H), 3.92 (s,3H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.45 (dd, J=13.8 and 6.0 Hz, 1H).

Preparation of(S)-4-(2-(2-phenylthiazol-4-yl)-2-(4-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamicacid (31): (S)-methyl5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carboxylate,30, (323 mg, 0.68 mmol) and tin (II) chloride (612 mg, 2.72 mmol) aredissolved in EtOH and the solution is brought to reflux. The solvent isremoved in vacuo and the resulting residue is dissolved in EtOAc. Asaturated solution of NaHCO₃ is added and the solution is stirred 1hour. The organic layer is separated and the aqueous layer extractedtwice with EtOAc. The combined organic layers are dried (Na₂SO₄),filtered and concentrated to a residue which is dissolved in pyridine(10 mL) and treated with SO₃-pyridine (130 mg, 0.82 mmol). The reactionis stirred at room temperature for 5 minutes after which a 7% solutionof NH₄OH is added. The mixture is then concentrated and the resultingresidue is purified by reverse phase chromatography to afford 0.071 g ofthe desired product as the ammonium salt ¹H NMR (300 MHz, MeOH-d₄) δ7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7.03-7.13 (m, 4H),4.74 (t, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 2H).

Compounds according to the first aspect of Category V which comprise asubstituted or unsubstituted thiazol-2-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XII and described herein below inExample 12. Intermediate 32 can be prepared according to Scheme II andExample 2 by substituting cyclopropane-carbothioic acid amide forthiophene-2-carbothioic acid amide.

Example 124-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2-ylamino]ethyl}phenylsulfamicacid (35)

Preparation of(S)-1-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea(33): To a solution of(S)-1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethan-aminehydrobromide hydrobromide salt, 32, (4.04 g, 10.9 mmol) and CaCO₃ (2.18g, 21.8 mmol) in CCl₄/water (25 mL/20 mL) is added thiophosgene (1.5 g,13.1 mmol). The reaction is stirred at room temperature for 18 hoursthen diluted with CH₂Cl₂ and water. The layers are separated and theaqueous layer extracted with CH₂Cl₂. The combined organic layers arewashed with brine, dried (Na₂SO₄) and concentrated in vacuo to a residuewhich is subsequently treated with ammonia (0.5M in 1,4-dioxane, 120 mL)which is purified over silica to afford 2.90 g of the desired product asa red-brown solid. LC/MS ESI-347 (M−1).

Preparation of(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine(34):(S)-1-(1-(2-Cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea,32, (350 mg, 1.00 mmol) and 2-bromo-3′-methoxy-acetophenone (253 mg,1.10 mmol) are combined in 3 mL CH₃CN and heated to reflux for 24 hours.The mixture is concentrated and chromatographed to afford 0.172 g of theproduct as a yellow solid. LC/MS ESI+479 (M+1).

Preparation of4-{(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2-ylamino]ethyl}phenylsulfamicacid: (35):(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine,34, (0.172 g) is dissolved in 10 mL MeOH. A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere for 18 hours. The reaction mixture is filtered through a bedof CELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in 5 mL pyridine and treated with SO₃-pyridine (114mg). The reaction is stirred at room temperature for 5 minutes afterwhich 10 mL of a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.033 g of the desired product as the ammoniumsalt. ¹H (CD₃OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80 (m,2H), 5.02 (t, 1H, J=6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J=7.1 Hz), 2.36(q, 1H, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

The following are non-limiting examples of compounds encompassed withinthe first aspect of Category V.

(S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylamino)-2-(2-ethylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.91 (s, 1H), 7.08-7.10 (m, 3H), 6.99(d, J=8.7 Hz, 2H), 4.58 (t, J=6.9 Hz, 1H), 4.11 (d, J=2.7 Hz, 2H), 3.78(s, 3H), 3.14-3.28 (m, 2H), 3.06 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz,3H).

(S)-4-(2-{5-[1-N-(2-Methoxy-2-oxoethylcarbamoyl)-1-H-indol-3-yl]oxazol-2-ylamino}-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.63 (d, J=7.8 Hz, 1H), 7.37 (s, 1H),7.18-7.29 (m, 4H), 7.02-7.16 (m, 4H), 6.85 (s, 1H), 5.04-5.09 (m, 1H),4.85 (s, 3H), 3.27 (dd, J=13.5 and 8.1 Hz, 1H), 3.10 (m, J=13.5 and 8.1Hz, 1H), 2.69 (s, 3H).

4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.52 (dd, J=7.5 and 1.2 Hz, 1H),6.95-7.24 (m, 10H), 5.04-5.09 (m, 1H), 3.92 (s, 3H), 3.26 (dd, J=13.8and 8.4 Hz, 1H), 3.10 (dd, J=13.8 and 8.4 Hz, 1H), 2.72 (s, 3H).

4-((S)-2-(5-((S)-1-(tert-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.03-7.27 (m, 10H), 6.50 (s, 1H),4.95-5.00 (m, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.22 (dd, J=14.1 and 6.9 Hz,1H), 3.00-3.10 (m, 2H), 2.90 (dd, J=14.1 and 6.9 Hz, 1H), 2.72 (s, 3H),1.37 (s, 9H).

(S)-{4-{2-[5-(4-Methoxycarbonyl)phenyl]oxazol-2-ylamino}-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.99 (d, J=7.5 Hz, 2H), 7.56-7.59 (m,2H), 7.23-7.24 (m, 1H), 7.08-7.14 (m, 4H), 6.83 (d, J=10.2 Hz, 1H), 5.08(t, J=6.0 Hz, 1H), 3.91 (s, 3H), 3.25-3.35 (m, 1H), 3.09-3.13 (m, 1H),2.73 (s, 3H).

(S)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.03-7.28 (m, 8H), 6.79-6.83 (m, 1H),5.70 (s, 1H), 4.99-5.06 (m, 2H), 4.41 (d, J=2.1 Hz, 2H), 3.80 (s, 3H),3.27-3.37 (m, 1H), 3.03-3.15 (m, 1H), 2.71 (s, 3H).

(S)-4-(2-(2-Methylthiazole-4-yl)-2-(5-phenyloxazole-2-ylamino)ethyl)phenyl-sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.45 (d, J=8.7 Hz, 2H), 7.33 (t, J=7.8Hz, 2H), 7.18-7.22 (m, 1H), 7.10-7.14 (m, 6H), 7.04 (s, 1H), 5.04-5.09(m, 1H), 3.26 (dd, J=13.8 and 6.3 Hz, 1H), 3.10 (dd, J=13.8 and 6.3 Hz,1H), 2.70 (s, 3H).

4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylamino)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80 (m,2H), 5.02 (t, 1H, J=6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J=7.1 Hz), 2.36(q, 1H, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

(S)-4-(2-(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2-ylamino)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.79-7.74 (m, 2H), 7.14-7.03 (m, 7H), 7.21 (s, 1H),6.79 (s, 1H), 5.08 (t, 1H, J=6.6 Hz), 3.29-3.12 (m, 2H), 2.40 (q, 2.40,J=5.1 Hz), 1.23-1.18 (m, 2H), 1.08-1.02 (m, 2H).

4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylamino)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.89-7.87 (d, 1H, J=7.6 Hz), 7.28 (t, 1H, J=7.0 Hz),7.10-6.96 (m, 8H), 5.03 (t, 1H, J=6.9 Hz), 3.90 (s, 1H), 3.19 (q, 2H,J=6.6 Hz), 2.38 (q, 1H, J=4.8 Hz), 1.21-1.14 (m, 2H), 1.06-1.00 (m, 2H).

4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2-ylamino)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 8.06-8.02 (q, 2H, J=6.9 Hz), 7.12-6.95 (m, 7H), 6.88(s, 1H), 5.11 (t, 1H, J=6.9 Hz), 3.22-3.15 (m, 2H), 2.38 (q, 1H, J=4.8Hz), 1.22-1.15 (m, 2H), 1.06-1.02 (m, 2H).

(S)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.22-7.17 (m, 3H), 7.09-6.97 (m, 5H), 6.78-6.66 (m,3H), 3.77 (s, 2H), 3.75 (s, 3H), 3.20-3.07 (m, 2H), 2.35 (q, 1H, J=4.8Hz), 1.19-1.13 (m, 2H), 1.03-1.00 (m, 2H).

(S)-{5-[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methyl-2H-[1,2,4]triazole-3-yl}carbamicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 6.97-7.08 (m, 5H), 3.71(s, 3H), 3.51 (s, 3H), 3.15 (dd, J=13.5 and 6.3 Hz, 1H), 3.02-3.07 (m,3H), 1.40 (t, J=6.6 Hz, 3H).

The second aspect of Category V of the present disclosure relates tocompounds having the formula:

wherein R¹ is a substituted or unsubstituted heteroaryl and R⁴ issubstituted or unsubstituted phenyl and substituted or unsubstitutedheteroaryl as further described herein below in Table X.

TABLE X No. R⁴ R¹ 471 phenyl 4-(methoxycarbonyl)thiazol-5-yl 472 phenyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 473 phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 474 phenyl5-(2-methoxyphenyl)oxazol-2-yl 475 phenyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 476 phenyl5-[4-(methylcarboxy)phenyl]oxazol-2-yl 477 phenyl5-(3-methoxybenzyl)oxazol-2-yl 478 phenyl 5-(4-phenyl)oxazol-2-yl 479phenyl 5-(2-methoxyphenyl)thiazol-2-yl 480 phenyl5-(3-methoxyphenyl)thiazol-2-yl 481 phenyl5-(4-fluorophenyl)thiazol-2-yl 482 phenyl5-(2,4-difluorophenyl)thiazol-2-yl 483 phenyl5-(3-methoxybenzyl)thiazol-2-yl 484 phenyl4-(3-methoxyphenyl)thiazol-2-yl 485 phenyl4-(4-fluorophenyl)thiazol-2-yl 486 thiophene-2-yl4-(methoxycarbonyl)thiazol-5-yl 487 thiophene-2-yl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 488 thiophene-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 489thiophene-2-yl 5-(2-methoxyphenyl)oxazol-2-yl 490 thiophene-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 491thiophene-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl 492 thiophene-2-yl5-(3-methoxybenzyl)oxazol-2-yl 493 thiophene-2-yl5-(4-phenyl)oxazol-2-yl 494 thiophene-2-yl5-(2-methoxyphenyl)thiazol-2-yl 495 thiophene-2-yl5-(3-methoxyphenyl)thiazol-2-yl 496 thiophene-2-yl5-(4-fluorophenyl)thiazol-2-yl 497 thiophene-2-yl5-(2,4-difluorophenyl)thiazol-2-yl 498 thiophene-2-yl5-(3-methoxybenzyl)thiazol-2-yl 499 thiophene-2-yl4-(3-methoxyphenyl)thiazol-2-yl 500 thiophene-2-yl4-(4-fluorophenyl)thiazol-2-yl 501 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl 502 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 503 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 504cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl 505 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 506cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl 507 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl 508 cyclopropyl 5-(4-phenyl)oxazol-2-yl509 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl 510 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl 511 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl 512 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl 513 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl 514 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl 515 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the second aspect of Category V which comprise asubstituted or unsubstituted thiazol-4-yl unit for R¹ can be prepared bythe procedure outlined in Schemes XIII, XIV, and XV and described hereinbelow in Examples 13, 14, and 15.

Example 13(S)-4-(2-(5-Methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)phenylsulfamicacid (41)

Preparation of [3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester (36): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g,4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). Thereaction mixture is stirred at 0° C. for 20 minutes then filtered. Thefiltrate is treated with an ether solution of diazomethane (˜16 mmol) at0° C. The reaction mixture is stirred at room temperature for 3 hoursand concentrated. The residue is dissolved in EtOAc and washedsuccessively with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue is purified over silica(hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product asa slightly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=8.7 Hz,2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49(s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz,1H), 1.41 (s, 9H).

Preparation of [3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester (37): To a 0° C. solution of[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester,36, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr(0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5hours and quenched at 0° C. with saturated aqueous Na₂CO₃. The mixtureis extracted with EtOAc (3×25 mL) and the combined organic extracts arewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo toafford 0.400 g of the desired product that is used in the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 8.20 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanaminehydrobromide salt (38): A mixture of[3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acid tert-butylester, 37, (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol),in CH₃CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooledto room temperature and diethyl ether (50 mL) is added to the solutionand the precipitate that forms is collected by filtration. The solid isdried under vacuum to afford 1.059 g (63%) of the desired product.ESI+MS 326 (M+1).

Preparation of(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole (39):To a solution of(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromidesalt, 38, (2.03 g, 5 mmol) and CaCO₃ (1 g, 10 mmol) in CCl₄/water(10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). The reaction isstirred at room temperature for 18 hours then diluted with CH₂Cl₂ andwater. The layers are separated and the aqueous layer extracted withCH₂Cl₂. The combined organic layers are washed with brine, dried(Na₂SO₄) and concentrated in vacuo to a residue that is purified oversilica (CH₂Cl₂) to afford 1.71 g (93% yield) of the desired product.ESI+MS 368 (M+1).

Preparation of(S)-5-methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazol-2-amine(40): A solution of(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole, 39,(332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in EtOH (5mL) is refluxed for 2 hours. The solvent is removed under reducedpressure, the residue is dissolved in POCl₃ (3 mL) and the resultingsolution is stirred at room temperature for 18 hours after which thesolution is heated to 50° C. for 2 hours. The solvent is removed invacuo and the residue is dissolved in EtOAc (40 mL) and the resultingsolution is treated with 1N NaOH until the pH remains approximately 8.The solution is extracted with EtOAc. The combined aqueous layers arewashed with EtOAc, the organic layers combined, washed with brine, driedover MgSO₄, filtered, and concentrated in vacuo to afford 0.345 g (93%yield) of the desired product as a yellow solid. ¹H NMR (CDCl₃) 8.09 (d,J=8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H),3.59 (m, 2H), 2.49 (s, 3H). ESI+MS 424 (M+1).

Preparation of(S)-4-[2-(5-methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenylsulfamicacid (41):(S)-5-Methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazol-2-amine,40, (0.404 g, 0.954 mmol) is dissolved in MeOH (5 mL). Pd/C (50 mg, 10%w/w) is added and the mixture is stirred under a hydrogen atmosphereuntil the reaction is judged to be complete. The reaction mixture isfiltered through a bed of CELITE™ and the solvent removed under reducedpressure. The crude product is dissolved in pyridine (4 mL) and treatedwith SO₃-pyridine (0.304 g, 1.91 mmol). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH (50 mL) isadded. The mixture is then concentrated and the resulting residue ispurified by reverse phase preparative HPLC to afford 0.052 g (11% yield)of the desired product as the ammonium salt. ¹H(CD₃OD): δ 8.00-7.97 (m,2H), 7.51-7.47 (m, 3H), 7.23 (s, 1H), 7.11-7.04 (q, 4H, J=9.0 Hz), 5.18(t, 1H, J=7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 3H). ESI− MS 472 (M−1).

Example 144-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (44)

Preparation of(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea(42): To a solution of(S)-2-(4-nitrophenyl)-1-(thiophen-2-ylthiazol-4-yl)ethanaminehydrobromide salt, 8, (1.23 g, 2.98 mmol) and CaCO₃ (0.597 g, 5.96 mmol)in CCl₄/water (10 mL/5 mL) is added thiophosgene (0.412 g, 3.58 mmol).The reaction is stirred at room temperature for 18 hours then dilutedwith CH₂Cl₂ and water. The layers are separated and the aqueous layerextracted with CH₂Cl₂. The combined organic layers are washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to a residue which issubsequently treated with ammonia (0.5M in 1,4-dioxane, 29.4 mL, 14.7mmol) which is purified over silica to afford 0.490 g of the desiredproduct as a red-brown solid. ESI+MS 399 (M+1).

Preparation of4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine(43):(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea,42, (265 mg, 0.679 mmol) is treated with bromo-2′-methoxyacetophenone(171 mg, 0.746 mmol) to afford 0.221 g of the product as a yellow solid.ESI+MS 521 (M+1).

Preparation on4-{(S)-2-[4-(2-methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (44):4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine,43, (0.229 g) is dissolved in 12 mL MeOH. A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere for 18 hours. The reaction mixture is filtered through a bedof CELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in 6 mL pyridine and treated with SO₃-pyridine (140mg). The reaction is stirred at room temperature for 5 minutes afterwhich 10 mL of a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.033 g of the desired product as the ammoniumsalt. ¹H(CD₃OD): δ 7.96-7.93 (m, 1H), 7.60-7.55 (m, 2H), 7.29-7.23 (m,1H), 7.18-6.95 (m, 9H), 5.15 (t, 1H, J=6.9 Hz), 3.90 (s, 3H), 3.35-3.24(m, 2H).

Compounds according to the second aspect of Category V which comprise asubstituted or unsubstituted oxazol-2-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XV and described herein below inExample 15. Intermediate 39 can be prepared according to Scheme XIII andExample 13.

Example 154-{(S)-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamicacid (46)

Preparation of[5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethyl]amine(45): A mixture of(S)-4-(isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole, 39, (300mg, 0.81 mmol), 1-azido-1-(3-methoxyphenyl)ethanone (382 mg, 2.0 mmol)and PPh₃ (0.8 g, polymer bound, ˜3 mmol/g) in dioxane (6 mL) is heatedat 90° C. for 20 minutes. The reaction solution is cooled to roomtemperature and the solvent removed in vacuo and the resulting residueis purified over silica to afford 300 mg (74% yield) of the desiredproduct as a yellow solid. ¹H NMR (300 MHz, MeOH-d₄) δ 8.02 (d, J=7.2Hz, 2H), 7.92-7.99 (m, 2H), 7.42-7.47 (m, 3H), 7.22-7.27 (m, 3H),6.69-7.03 (m, 4H), 6.75-6.78 (m, 1H), 5.26 (t, J=6.3 Hz, 1H), 3.83 (s,4H), 3.42-3.45 (m, 2H).

Preparation of4-{(S)-2-[5-(3-methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamicacid (46):[5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethyl]amine,45, (300 mg, 0.60 mmol) is dissolved in MeOH (15 mL). A catalytic amountof Pd/C (10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (10 mL) and treated with SO₃-pyridine(190 mg, 1.2 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.042 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.99 (d, J=7.5 Hz, 2H), 7.46-7.50 (m,3H), 7.23-7.29 (m, 3H), 7.04-7.12 (m, 6H), 6.78 (dd, J=8.4 and 2.4 Hz,1H), 5.16 (t, J=6.6 Hz, 1H), 3.81 (s, 3H), 3.29-3.39 (m, 1H), 3.17 (dd,J=13.8 and 8.1 Hz, 1H).

Further to the preparation of compounds which encompass Category V ofthe present disclosure, compounds of the present disclosure comprisingR¹ units having non-exemplified units can be prepared by modifying theprocedures described herein above. For example, compounds of Category Vcomprising substituted or unsubstituted [1,2,4]triazole-3-yl units canbe prepared by s

The following are non-limiting examples of the second aspect of CategoryV of the present disclosure.

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H(CD₃OD): δ 7.97-7.94 (m, 2H), 7.73-7.70 (m, 2H), 7.44-7.39 (m,6H), 7.25 (s, 1H), 7.12 (s, 4H), 5.29 (t, 1H, J=6.9 Hz), 3.35-3.26 (m,2H).

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.59-7.54 (m, 2H), 7.17-7.03 (m, 6H), 5.13 (t, 1H,J=7.2 Hz), 3.32-3.13 (m, 2H), 2.81 (t, 2H, J=7.4 Hz), 1.76-1.63 (h, 6H,J=7.4 Hz), 0.97 (t, 3H, J=7.3 Hz).

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H(CD₃OD): 6 (m, 2H), 7.49-7.45 (m, 2H), 7.26-7.16 (m, 5H),7.05-6.94 (m, 6H), 5.04 (t, 1H, J=7.1 Hz), 4.07 (s, 2H), 3.22-3.04 (m,2H).

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 8.08-8.05 (m, 1H), 7.89-7.80 (m, 2H), 7.55-7.43 (m,6H), 7.11-7.00 (m, 6H), 5.08 (t, 1H, J=7.1 Hz), 4.63 (s, 2H), 3.26-3.08(m, 2H).

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.48-7.44 (m, 2H), 7.03-6.92 (m, 6H), 5.02 (t, 1H,J=7.2 Hz), 4.30 (s, 2H), 3.55 (s, 3H), 3.22-3.02 (m, 2H).

4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.60-7.56 (m, 2H), 7.19 (s, 1H), 7.15-7.12 (m, 2H),7.09-7.03 (q, 4H, J=8.7 Hz), 5.14 (t, 1H, J=7.2 Hz), 4.28 (s, 2H),3.33-3.14 (m, 2H), 2.67 (s, 3H).

4-{(S)-2-[4-(2,4-Difluorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 8.06-8.02 (q, 1H, J=6.8 Hz), 7.59-7.54 (m, 2H),7.16-7.08 (m, 6H), 7.01-6.88 (m, 4H), 5.20 (t, 1H, J=7.0 Hz), 3.36-3.17(m, 2H).

(S)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 8.02-7.99 (m, 2H), 7.54-7.45 (m, 4H), 7.26 (s, 1H),7.08 (s, 4H), 5.26 (t, 1H, J=6.9 Hz), 4.35-4.28 (q, 2H, J=6.9 Hz),3.38-3.18 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).

(S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.96 (m, 2H), 7.50-7.46 (m, 3H), 7.21 (s, 1H),7.10-7.04 (m, 4H), 6.37 (s, 1H), 5.09 (t, 1H, J=6.9 Hz), 4.17-4.10 (q,2H, J=7.1 Hz), 3.54 (s, 2H), 3.35-3.14 (m, 2H), 1.22 (t, 3H, J=7.1 Hz).

(S)-4-{2-[4-(4-acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 8.11 (m, 2H), 7.82-7.80 (m, 2H), 7.71-7.61 (m, 6H),7.40 (s, 1H), 7.23 (s, 4H), 5.32 (t, 1H, J=7.0 Hz), 3.51-3.35 (m, 2H),2.28 (s, 3H).

(S)-4-[2-(4-phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenyl-sulfamicacid: ¹H(CD₃OD): δ 8.03-7.99 (m, 2H), 7.75-7.72 (d, 2H, J=8.4 Hz),7.53-7.48 (m, 3H), 7.42 (m, 4H), 7.12 (s, 4H), 6.86 (s, 1H), 5.23 (t,1H, J=7.2 Hz), 3.40-3.27 (m, 2H).

(S)-4-{2-[4-(4-(methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 8.04-8.00 (m, 4H), 7.92-7.89 (d, 2H, J=9.0 Hz),7.53-7.49 (m, 3H), 7.30 (s, 1H), 7.15 (s, 4H), 7.05 (s, 1H), 5.28 (t,1H, J=6.9 Hz), 3.93 (s, 3H), 3.35-3.24 (m, 2H).

4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.43-7.38 (m, 2H), 7.26 (s, 1H), 7.00-6.94 (m, 3H),6.89 (s, 4H), 5.02 (t, 1H, J=7.0 Hz), 4.16-4.09 (q, 2H, J=7.1 Hz),3.14-2.94 (m, 2H), 1.17 (t, 3H, J=7.1 Hz).

(S)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H),7.22 (s, 1H), 7.03-7.13 (m, 4H), 4.74 (t, J=6.6 Hz, 1H), 3.88 (s, 3H),3.28-3.42 (m, 2H).

(S)-4-[2-(5-Phenyloxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]-phenylsulfamic acid: ¹HNMR (300 MHz, MeOH-d₄) δ 7.94-7.96 (m, 2H), 7.45-7.49 (m, 5H), 7.32 (t,J=7.8 Hz, 2H), 7.12 (s, 1H), 7.19 (t, J=7.2 Hz, 1H), 7.12 (s, 4H), 7.05(s, 1H), 5.15 (t, J=6.4 Hz, 1H), 3.34 (dd, J=14.1 and 8.4 Hz, 1H), 3.18(dd, J=14.1 and 8.4 Hz, 1H).

(S)-4-{2-[5-(4-Acetamidophenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.92-7.94 (m, 2H), 7.55-7.58 (m, 2H),7.39-7.50 (m, 5H), 7.26 (s, 1H), 7.12 (s, 4H), 7.02 (s, 1H0), 5.14 (t,J=7.8 Hz, 1H), 3.13-3.38 (m, 2H), 2.11 (s, 3H).

4-((S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.97-7.99 (m, 2H), 7.54-7.62 (m, 1H),7.45-7.50 (m, 3H), 7.28 (s, 1H), 7.12 (s, 4H), 6.97-7.06 (m, 3H),5.15-5.20 (m, 1H), 3.28-3.40 (m, 1H), 3.20 (dd, J=13.8 and 8.4 Hz, 1H).

4-{(S)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophen-2-yl)thiazole-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.55-7.60 (m, 2H), 7.26 (t, J=8.1 Hz,1H), 7.21 (s, 1H), 7.04-7.15 (m, 8H), 6.77-6.81 (m, 1H), 5.10 (t, J=6.3Hz, 1H), 3.81 (s, 3H), 3.29-3.36 (m, 1H), 3.15 (dd, J=14.1 and 8.4 Hz,1H).

(S)-4-[2-(4,6-Dimethylpyrimidin-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.00-7.10 (m, 5H), 6.44 (s, 1H), 5.50(t, J=7.2 Hz, 1H), 3.04-3.22 (m, 2H), 2.73 (s, 3H), 2.27 (s, 6H).

(S)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.44 (d, J=8.4 Hz, 2H), 6.97-7.10 (m,4H), 5.61 (s, 1H), 5.40-5.49 (m, 1H), 3.10-3.22 (m, 2H), 2.73 (s, 3H),2.13 (s, 3H).

The first aspect of Category VI of the present disclosure relates tocompounds having the formula:

wherein R¹ is heteroaryl and R⁴ is further described herein below inTable XI.

TABLE XI No. R⁴ R¹ 516 phenyl 4-(methoxycarbonyl)thiazol-5-yl 517 phenyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 518 phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 519 phenyl5-(2-methoxyphenyl)oxazol-2-yl 520 phenyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 521 phenyl5-[4-(methylcarboxy)phenyl]oxazol-2-yl 522 phenyl5-(3-methoxybenzyl)oxazol-2-yl 523 phenyl 5-(4-phenyl)oxazol-2-yl 524phenyl 5-(2-methoxyphenyl)thiazol-2-yl 525 phenyl5-(3-methoxyphenyl)thiazol-2-yl 526 phenyl5-(4-fluorophenyl)thiazol-2-yl 527 phenyl5-(2,4-difluorophenyl)thiazol-2-yl 528 phenyl5-(3-methoxybenzyl)thiazol-2-yl 529 phenyl4-(3-methoxyphenyl)thiazol-2-yl 530 phenyl4-(4-fluorophenyl)thiazol-2-yl 531 thiophene-2-yl4-(methoxycarbonyl)thiazol-5-yl 532 thiophene-2-yl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 533 thiophene-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 534thiophene-2-yl 5-(2-methoxyphenyl)oxazol-2-yl 535 thiophene-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 536thiophene-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl 537 thiophene-2-yl5-(3-methoxybenzyl)oxazol-2-yl 538 thiophene-2-yl5-(4-phenyl)oxazol-2-yl 539 thiophene-2-yl5-(2-methoxyphenyl)thiazol-2-yl 540 thiophene-2-yl5-(3-methoxyphenyl)thiazol-2-yl 541 thiophene-2-yl5-(4-fluorophenyl)thiazol-2-yl 542 thiophene-2-yl5-(2,4-difluorophenyl)thiazol-2-yl 543 thiophene-2-yl5-(3-methoxybenzyl)thiazol-2-yl 544 thiophene-2-yl4-(3-methoxyphenyl)thiazol-2-yl 545 thiophene-2-yl4-(4-fluorophenyl)thiazol-2-yl 546 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl 547 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl 548 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl 549cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl 550 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl 551cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl 552 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl 553 cyclopropyl 5-(4-phenyl)oxazol-2-yl554 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl 555 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl 556 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl 557 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl 558 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl 559 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl 560 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the first aspect of Category VI can be preparedby the procedure outlined in Scheme XVI and described herein below inExample 16.

Example 164-((S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)oxazol-4-yl)ethyl)phenylsulfamicacid (49)

Preparation of(S)-2-(4-nitrophenyl)-1-[(thiophene-2-yl)oxazol-4-yl]ethanaminehydrobromide salt (47): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (38.7 g, 100mmol), and thiophene-2-carboxamide (14 g, 110 mmol) (available from AlfaAesar) in CH₃CN (500 mL) is refluxed for 5 hours. The reaction mixtureis cooled to room temperature and diethyl ether (200 mL) is added to thesolution. The precipitate which forms is collected by filtration. Thesolid is dried under vacuum to afford the desired product which can beused for the next step without purification.

Preparation of2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)oxazol-4-yl]ethyl}acetamide(48): To a solution of(S)-2-(4-nitrophenyl)-1-[(thiophene-2-yl)oxazol-4-yl]ethanamine HBr, 47,(3.15 g, 10 mmol) 3-chlorophenyl-acetic acid (1.70 g, 10 mmol) and1-hydroxybenzotriazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 mL) at 0°C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.90g, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford the desired product which is used without furtherpurification.

Preparation of-((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)oxazol-4-yl)ethyl)phenylsulfamicacid (49):2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)oxazol-4-yl]ethyl}acetamide,48, (3 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10%w/w) is added and the mixture is stirred under a hydrogen atmosphere 18hours. The reaction mixture is filtered through a bed of CELITE™ and thesolvent is removed under reduced pressure. The crude product isdissolved in pyridine (12 mL) and treated with SO₃-pyridine (0.157 g).The reaction is stirred at room temperature for 5 minutes after which a7% solution of NH₄OH is added. The mixture is then concentrated and theresulting residue can be purified by reverse phase chromatography toafford the desired product as the ammonium salt.

The second aspect of Category VI of the present disclosure relates tocompounds having the formula:

wherein R¹ is aryl and R² and R³ are further described herein below inTable XII.

TABLE XII No. R² R³ R¹ 561 methyl hydrogen phenyl 562 methyl hydrogenbenzyl 563 methyl hydrogen 2-fluorophenyl 564 methyl hydrogen3-fluorophenyl 565 methyl hydrogen 4-fluorophenyl 566 methyl hydrogen2-chlorophenyl 567 methyl hydrogen 3-chlorophenyl 568 methyl hydrogen4-chlorophenyl 569 ethyl hydrogen phenyl 570 ethyl hydrogen benzyl 571ethyl hydrogen 2-fluorophenyl 572 ethyl hydrogen 3-fluorophenyl 573ethyl hydrogen 4-fluorophenyl 574 ethyl hydrogen 2-chlorophenyl 575ethyl hydrogen 3-chlorophenyl 576 ethyl hydrogen 4-chlorophenyl 577thiene-2-yl hydrogen phenyl 578 thiene-2-yl hydrogen benzyl 579thiene-2-yl hydrogen 2-fluorophenyl 580 thiene-2-yl hydrogen3-fluorophenyl 581 thiene-2-yl hydrogen 4-fluorophenyl 582 thiene-2-ylhydrogen 2-chlorophenyl 583 thiene-2-yl hydrogen 3-chlorophenyl 584thiene-2-yl hydrogen 4-chlorophenyl

Compounds according to the second aspect of Category VI can be preparedby the procedure outlined in Scheme XVII and described herein below inExample 17.

Example 17{4-[2-(S)-(4-Ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamicacid (52)

Preparation of (S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine(50): A mixture of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acidtert-butyl ester, 1, (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1mL, 36 mmol) in CH₃CN (500 mL) is refluxed for 18 hours. The reactionmixture is cooled to room temperature and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration and isused without further purification.

Preparation ofN-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide(51): To a solution of(S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine, 50, (2.9 g, 11mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hydroxybenzotriazole(HOBt) (0.94 g, 7.0 mmol) in DMF (100 mL) at 0° C., is added1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (2.68 g, 14 mmol)followed by triethylamine (6.0 mL, 42 mmol). The mixture is stirred at0° C. for 30 minutes then at room temperature overnight. The reactionmixture is diluted with water and extracted with EtOAc. The combinedorganic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, waterand brine, and dried over Na₂SO₄. The solvent is removed in vacuo toafford the desired product which is used without further purification.

Preparation of{4-[2-(S)-(4-ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamicacid (52):N-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide,51, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.177 g, 1.23). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (10 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford the desired product as the ammonium salt.

Regulation of HPTP-β provides a method for modulating the activity ofangiopoietin receptor-type tyrosine kinase Tie-2, and thereby mediate,affect, or otherwise control disease states related to angiogenesiswherein angiogenesis is improperly regulated by the human body. Thecompounds of the present disclosure serve as a method for providingregulation of angiogenesis. As such the present disclosure addressesseveral unmet medical needs, inter alia;

-   1) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder wherein angiogenesis is    elevated;-   2) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder; and-   3) Providing compositions effective human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder wherein angiogenesis is    decreased.

For purposes of the present disclosure the term “regulate” is defined asincluding, but is not limited to, up-regulate or down-regulate, to fix,to bring order or uniformity, to govern, or to direct by various means.In one aspect, an antibody may be used in a method for the treatment ofan “angiogenesis elevated disorder” or “angiogenesis reduced disorder”.As used herein, an “angiogenesis elevated disorder” is one that involvesunwanted or elevated angiogenesis in the biological manifestation of thedisease, disorder, and/or condition; in the biological cascade leadingto the disorder; or as a symptom of the disorder. Similarly, the“angiogenesis reduced disorder” is one that involves wanted or reducedangiogenesis in the biological manifestations. This “involvement” ofangiogenesis in an angiogenesis elevated/reduced disorder includes, butis not limited to, the following:

-   1. The angiogenesis as a “cause” of the disorder or biological    manifestation, whether the level of angiogenesis is elevated or    reduced genetically, by infection, by autoimmunity, trauma,    biomechanical causes, lifestyle, or by some other causes.-   2. The angiogenesis as part of the observable manifestation of the    disease or disorder. That is, the disease or disorder is measurable    in terms of the increased or reduced angiogenesis. From a clinical    standpoint, angiogenesis indicates the disease; however,    angiogenesis need not be the “hallmark” of the disease or disorder.-   3. The angiogenesis is part of the biochemical or cellular cascade    that results in the disease or disorder. In this respect, regulation    of angiogenesis may interrupt the cascade, and may control the    disease. Non-limiting examples of angiogenesis regulated disorders    that may be treated by the present disclosure are herein described    below.

Formulations

The present disclosure also relates to compositions or formulations thatcomprise one or more human protein tyrosine phosphatase beta (HPTP-β)inhibitors as disclosed herein. In general, the disclosed compositionscomprise:

-   -   a) an effective amount of one or more phenylsufamic acids or        salts thereof according to the present disclosure that are        effective as human protein tyrosine phosphatase beta (HPTP-β)        inhibitors; and    -   b) one or more excipients.

For the purposes of the present disclosure the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent disclosure and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present disclosure have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

Non-limiting examples of disclosed compositions include:

-   -   a) from about 0.001 mg to about 1000 mg of one or more        phenylsulfamic acids or salts thereof according to the present        disclosure; and    -   b) one or more excipients.

Another example of disclosed compositions includes:

-   -   a) from about 0.01 mg to about 100 mg of one or more        phenylsulfamic acids or salts thereof according to the present        disclosure; and    -   b) one or more excipients.

A further example of disclosed compositions includes:

-   -   a) from about 0.1 mg to about 10 mg of one or more        phenylsulfamic acids or salts thereof according to the present        disclosure; and    -   b) one or more excipients.

The term “effective amount” as used herein means “an amount of one ormore phenylsulfamic acids, effective at dosages and for periods of timenecessary to achieve the desired or therapeutic result.” An effectiveamount may vary according to factors known in the art, such as thedisease state, age, sex, and weight of the human or animal beingtreated. Although particular dosage regimes may be described in examplesherein, a person skilled in the art would appreciated that the dosageregime may be altered to provide optimum therapeutic response. Thus, itis not possible to specify an exact “effective amount.” For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. In addition, the compositions of the present disclosure canbe administered as frequently as necessary to achieve a therapeuticamount.

Method of Use

The present disclosure relates to methods for regulating angiogenesis ina human comprising administering to a human one or more of the disclosedcompounds.

One example of the disclosed methods includes a method for treating anangiogenesis regulated disorder in a subject, wherein the angiogenesisregulated disorder is an angiogenesis elevated disorder, and saiddisorder is chosen from diabetic retinopathy, macular degeneration,cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum,Paget's disease, vein occlusion, artery occlusion, carotid obstructivedisease, chronic uveitis/vitritis, mycobacterial infections, Lyme'sdisease, systemic lupus erythematosis, retinopathy of prematurity,Eales' disease, Behcet's disease, infections causing a retinitis orchoroiditis, presumed ocular histoplasmosis, Best's disease, myopia,optic pits, Stargardt's disease, pars planitis, chronic retinaldetachment, hyperviscosity syndrome, toxoplasmosis, trauma andpost-laser complications, diseases associated with rubeosis, andproliferative vitreoretinopathy.

Another example of the disclosed methods includes a method for treatingan angiogenesis regulated disorder in a subject, wherein theangiogenesis regulated disorder is an angiogenesis elevated disorder,and said disorder is chosen from inflammatory bowel diseases such asCrohn's disease and ulcerative colitis, psoriasis, sarcoidosis,rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, orhereditary hemorrhagic telangiectasia, solid or blood borne tumors andacquired immune deficiency syndrome.

A further example of the disclosed methods includes a method fortreating an angiogenesis regulated disorder in a subject wherein theangiogenesis regulated disorder is an angiogenesis reduced disorder andchosen from skeletal muscle and myocardial ischemia, stroke, coronaryartery disease, peripheral vascular disease, coronary artery disease.

A yet further example of the disclosed methods includes a method ofvascularizing ischemic tissue. As used herein, “ischemic tissue,” meanstissue that is deprived of adequate blood flow. Examples of ischemictissue include, but are not limited to, tissue that lack adequate bloodsupply resulting from myocardial and cerebral infarctions, mesenteric orlimb ischemia, or the result of a vascular occlusion or stenosis. In oneexample, the interruption of the supply of oxygenated blood may becaused by a vascular occlusion. Such vascular occlusion may be caused byarteriosclerosis, trauma, surgical procedures, disease, and/or otheretiologies. Also included within the methods of treatment of the presentdisclosure is the treatment of skeletal muscle and myocardial ischemia,stroke, coronary artery disease, peripheral vascular disease, coronaryartery disease.

A still further example of the disclosed methods includes a method ofrepairing tissue. As used herein, “repairing tissue” means promotingtissue repair, regeneration, growth, and/or maintenance including, butnot limited to, wound repair or tissue engineering. One skilled in theart appreciates that new blood vessel formation is required for tissuerepair. In turn, tissue may be damaged by, including, but not limitedto, traumatic injuries or conditions including arthritis, osteoporosisand other skeletal disorders, and burns. Tissue may also be damaged byinjuries due to surgical procedures, irradiation, laceration, toxicchemicals, viral infection or bacterial infections, or burns. Tissue inneed of repair also includes non-healing wounds. Examples of non-healingwounds include non-healing skin ulcers resulting from diabeticpathology; or fractures that do not heal readily.

The disclosed compounds are also suitable for use in effecting tissuerepair in the context of guided tissue regeneration (GTR) procedures.Such procedures are currently used by those skilled in the arts toaccelerate wound healing following invasive surgical procedures.

A yet still further example of the disclosed methods includes a methodof promoting tissue repair characterized by enhanced tissue growthduring the process of tissue engineering. As used herein, “tissueengineering” is defined as the creation, design, and fabrication ofbiological prosthetic devices, in combination with synthetic or naturalmaterials, for the augmentation or replacement of body tissues andorgans. Thus, the present methods may be used to augment the design andgrowth of human tissues outside the body for later implantation in therepair or replacement of diseased tissues. For example, antibodies maybe useful in promoting the growth of skin graft replacements that areused as a therapy in the treatment of burns.

Other examples of the tissue engineering example of the disclosedmethods includes in cell-containing or cell-free devices that induce theregeneration of functional human tissues when implanted at a site thatrequires regeneration. As discussed herein, biomaterial-guided tissueregeneration may be used to promote bone re-growth in, for example,periodontal disease. Thus, antibodies may be used to promote the growthof reconstituted tissues assembled into three-dimensional configurationsat the site of a wound or other tissue in need of such repair.

A yet further example of the tissue engineering example of the disclosedmethods, the compounds disclosed herein can be included in external orinternal devices containing human tissues designed to replace thefunction of diseased internal tissues. This approach involves isolatingcells from the body, placing them with structural matrices, andimplanting the new system inside the body or using the system outsidethe body. For example, antibodies may be included in a cell-linedvascular graft to promote the growth of the cells contained in thegraft. It is envisioned that the methods of the disclosure may be usedto augment tissue repair, regeneration and engineering in products suchas cartilage and bone, central nervous system tissues, muscle, liver,and pancreatic islet (insulin-producing) cells.

The present disclosure also relates to the use of the disclosedphenylsulfamic acids in the manufacture of a medicament for promotingthe growth of skin graft replacements.

The present disclosure also relates to the use of the disclosedphenylsulfamic acids according to the present disclosure in themanufacture of a medicament for use in effecting tissue repair in thecontext of guided tissue regeneration (GTR) procedures.

The disclosed compounds can be used in the manufacture of one or moremedicaments, non-limiting examples of these medicaments are:

Medicaments for the treatment an angiogenesis regulated disorder in asubject, wherein the angiogenesis regulated disorder is an angiogenesiselevated disorder.

Medicaments for the treatment an angiogenesis regulated disorder in asubject, wherein the angiogenesis regulated disorder is an angiogenesiselevated disorder chosen from Crohn's disease and ulcerative colitis,psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas,Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia,solid or blood borne tumors and acquired immune deficiency syndrome.

Medicaments useful for the purposes of tissue engineering therebyinducing enhanced tissue growth.

Medicaments for the treatment an angiogenesis regulated disorder in asubject, wherein the angiogenesis regulated disorder is an angiogenesisreduced disorder.

Procedures Screening Assays Using In Vitro and In Vivo Models ofAngiogenesis

Antibodies of the disclosed compounds may be screened in angiogenesisassays that are known in the art. Such assays include in vitro assaysthat measure surrogates of blood vessel growth in cultured cells orformation of vascular structures from tissue explants and in vivo assaysthat measure blood vessel growth directly or indirectly (Auerbach, R.,et al. (2003). Clin Chem 49, 32-40, Vailhe, B., et al. (2001). LabInvest 81, 439-452).

1. In Vitro Models of Angiogenesis

The in vitro models which are suitable for use in the present disclosureemploy cultured endothelial cells or tissue explants and measure theeffect of agents on “angiogenic” cell responses or on the formation ofblood capillary-like structures. Non-limiting examples of in vitroangiogenesis assays include but are not limited to endothelial cellmigration and proliferation, capillary tube formation, endothelialsprouting, the aortic ring explant assay and the chick aortic archassay.

2. In Vivo Models of Angiogenesis

The in vivo agents or antibodies which are suitable for use in thepresent disclosure are administered locally or systemically in thepresence or absence of growth factors (i.e. VEGF or angiopoietin 1) andnew blood vessel growth is measured by direct observation or bymeasuring a surrogate marker such as hemoglobin content or a fluorescentindicator. Non-limiting examples of in vitro angiogenesis assays includebut are not limited to chick chorioallantoic membrane assay, the cornealangiogenesis assay, and the MATRIGEL™ plug assay.

3. Procedures for Determining Vascularization of Ischemic Tissue.

Standard routine techniques are available to determine if a tissue is atrisk of suffering ischemic damage from undesirable vascular occlusion.For example, in myocardial disease these methods include a variety ofimaging techniques (e.g., radiotracer methodologies, x-ray, and MRI) andphysiological tests. Therefore, induction of angiogenesis as aneffective means of preventing or attenuating ischemia in tissuesaffected by or at risk of being affected by a vascular occlusion can bereadily determined

A person skilled in the art of using standard techniques can measure thevascularization of tissue. Non-limiting examples of measuringvascularization in a subject include SPECT (single photon emissioncomputed tomography); PET (positron emission tomography); MRI (magneticresonance imaging); and combination thereof, by measuring blood flow totissue before and after treatment. Angiography may be used as anassessment of macroscopic vascularity. Histologic evaluation may be usedto quantify vascularity at the small vessel level. These and othertechniques are discussed in Simons, et al., “Clinical trials in coronaryangiogenesis,” Circulation, 102, 73-86 (2000).

The following are non-limiting examples of HPTPβ (IC₅₀ μM) and PTP1B(IC₅₀ μM) activity is listed herein below in Table A.

TABLE A HPTPβ PTP1B Compound IC₅₀ μM IC₅₀ μM

  (S)-{4-[2-(4-Ethylthiazol-2-yl)-2-(phenylacetylamido)ethyl]-phenyl}sulfamic acid 0.05 22.9

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid 0.012 5.36

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid 0.0003 2.85

  (S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid 0.028 5.36

  (S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid 0.075 23.9

  (S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid 0.056 22.8

  (S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid 0.033 13.6

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenyl-sulfamic acid 0.04 6.57

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid 0.014 11.7

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid 0.008 4.05

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamic acid 0.002 10.4

  (S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic acid 0.028 15.5

  (S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic acid 0.037 25.4

  (S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid 0.0002 15.3

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid 0.003 16.9

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid 0.01 20.6

  (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid 0.006 16.0

  (S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid 0.002 0.53

  (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide]ethyl}phenylsulfamic acid 0.0020.254

  (S)-4-[2-(Benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid 0.042 19

While particular embodiments of the present disclosure have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this disclosure.

1. A compound having the formula:

wherein R is a substituted or unsubstituted thiazolyl unit having the formula:

R² and R³ are each independently chosen from: i) hydrogen; or ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; R⁴ is a unit chosen from: i) hydrogen; or ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; R¹ is substituted or unsubstituted phenyl, said substitutions are independently chosen from one or more halogen, C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl, —OR¹¹, —CN, —N(R¹¹)₂, —CO₂R¹¹, —C(O)N(R¹¹)₂, —NR¹¹C(O)R¹¹, —NO₂, —SO₂R¹¹, phenyl, benzyl, or two substitutions can be taken together to form a cycloalkyl, heterocyclic, or heteroaryl ring comprising from 3-7 atoms, said rings comprising one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; each R¹¹ is independently hydrogen; substituted or unsubstituted C₁-C₄ linear, C₃-C₄ branched, C₃-C₄ cyclic alkyl or substituted or unsubstituted phenyl or benzyl; or when R¹ is substituted by phenyl or benzyl, said phenyl or benzyl can be further substituted by halogen, C₁-C₃ linear alkyl, C₁-C₃ linear alkoxy, —CO₂R¹¹ and —NHCOR¹⁶; each R¹⁶ is independently hydrogen, methyl, or ethyl; L has the formula: —C(O)[C(R^(6a)R^(6b))]_(x)—; R^(6a) and R^(6b) are each independently: i) hydrogen; or ii) C₁-C₄ linear or C₃-C₄ branched alkyl; the index x is from 0 to 4; or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein the compounds are salts comprising cations chosen from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.
 3. The compound according to claim 1, wherein R has the formula:


4. The compound according to claim 3, wherein R² and R³ are each hydrogen or substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl.
 5. The compound according to claim 3, wherein R² is methyl and R³ is hydrogen.
 6. The compound according to claim 1, wherein R¹ is chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl.
 7. The compound according to claim 1, wherein L has the formula —C(O)CH₂—.
 8. The compound according to claim 1, wherein L has the formula —C(O)CH₂CH₂—.
 9. A compound having the formula:

wherein R is a substituted or unsubstituted thiazolyl unit having the formula:

R² and R³ are each independently chosen from: i) hydrogen; or ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; R⁴ is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; or iii) 5-member or 6-member heteroaryl, wherein the heteroaryl ring contains one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; R¹ is chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted 5-member or 6-member heteroaryl, wherein the heteroaryl ring contains one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; said substitutions are independently chosen from one or more halogen, C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl, —OR¹¹, —CN, —N(R¹¹)₂, —CO₂R¹¹, —C(O)N(R¹¹)₂, —NR¹¹C(O)R¹¹, —NO₂, —SO₂R¹¹, phenyl, benzyl, or two substitutions can be taken together to form a cycloalkyl, heterocyclic, or heteroaryl ring comprising from 3-7 atoms, said rings comprising one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; each R¹¹ is independently hydrogen; substituted or unsubstituted C₁-C₄ linear, C₃-C₄ branched, C₃-C₄ cyclic alkyl or substituted or unsubstituted phenyl or benzyl; or when R¹ is substituted by phenyl or benzyl, said phenyl or benzyl can be further substituted by halogen, C₁-C₃ linear alkyl, C₁-C₃ linear alkoxy, —CO₂R¹¹ and —NHCOR¹⁶; each R¹⁶ is independently hydrogen, methyl, or ethyl; L has the formula: —SO₂[C(R^(8a)R^(8b))]_(z)—; R^(8a) and R^(8b) are each independently: i) hydrogen; or ii) C₁-C₄ linear or C₃-C₄ branched alkyl; the index x is from 0 to 4; or a pharmaceutically acceptable salt thereof.
 10. The compound according to claim 9, wherein L is chosen from: i) —SO₂CH₂—; i) —SO₂CH₂CH₂—; or i) —SO₂CH₂CH₂CH₂—.
 11. The compound according to claim 9, wherein R⁴ is a heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl, [1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and [1,3,4]thiadiazol-2-yl.
 12. The compound according to claim 9, wherein R⁴ is thiophen-2-yl or thiophen-3-yl.
 13. The compound according to claim 9, wherein R¹ is substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl.
 14. The compound according to claim 9, wherein R¹ is substituted or unsubstituted phenyl.
 15. The compound according to claim 9, wherein R¹ is substituted or unsubstituted 5-member or 6-member heteroaryl.
 16. A compound having the formula:

wherein R⁴ is chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted 5-member or 6-member heteroaryl, wherein the heteroaryl ring contains one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; R¹ is substituted or unsubstituted 5-member or 6-member heteroaryl, wherein the heteroaryl ring contains one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; said substitutions are independently chosen from one or more halogen, C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl, —OR¹¹, —CN, —N(R¹¹)₂, —CO₂R¹¹, —C(O)N(R¹¹)₂, —NR¹¹C(O)R¹¹, —NO₂, —SO₂R¹¹, phenyl, benzyl, or two substitutions can be taken together to form a cycloalkyl, heterocyclic, or heteroaryl ring comprising from 3-7 atoms, said rings comprising one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; each R¹¹ is independently hydrogen; substituted or unsubstituted C₁-C₄ linear, C₃-C₄ branched, C₃-C₄ cyclic alkyl or substituted or unsubstituted phenyl or benzyl; or when R¹ is substituted by phenyl or benzyl, said phenyl or benzyl can be further substituted by halogen, C₁-C₃ linear alkyl, C₁-C₃ linear alkoxy, —CO₂R¹¹ and —NHCOR¹⁶; each R¹⁶ is independently hydrogen, methyl, or ethyl.
 17. The compound according to claim 16, wherein R¹ is chosen from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl, [1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and [1,3,4]thiadiazol-2-yl.
 18. The compound according to claim 16, wherein R¹ is a phenyl or benzyl substituted 5-member or 6-member heteroaryl, wherein the heteroaryl ring contains one or more heteroatoms chosen from oxygen, nitrogen, or sulfur; wherein the phenyl ring or benzyl aryl ring can be further substituted with halogen, C₁-C₃ linear alkyl, C₁-C₃ linear alkoxy, —CO₂R¹¹ and —NHCOR¹⁶; each R¹⁶ is independently hydrogen, methyl, or ethyl.
 19. The compound according to claim 16, wherein R⁴ is substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl.
 20. The compound according to claim 16, wherein R¹ is [1,3,4]thiadiazol-2-yl substituted with methyl, ethyl, propyl, benzyl, 3-methoxybenzyl, naphthalen-1-ylmethyl, (methoxycarbonyl)methyl, or (2-methylthiazol-4-yl)methyl. 